HtrA Inhibitors and CagA Inhibitors and Use Thereof

ABSTRACT

The present application relates to new HtrA inhibitors and use thereof. Additionally, the present application also relates to new peptides for inhibiting CagA and use thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 62/788,955 filed Jan. 7, 2019 entitled “Method andSystem to Target Bacteria with Antibacterial Compounds from theMicrobiota”; U.S. Provisional Patent Application No. 62/788,957 filedJan. 7, 2019 entitled “Method and System for Protecting Cell JunctionsProteins of Intestinal Epithelium”; U.S. Provisional Patent ApplicationNo. 62/788,958 filed Jan. 7, 2019 entitled “Method and System forTargeting Microbiota Proteins Mimicking Host Proteins”; U.S. ProvisionalPatent Application No. 62/788,939 filed Jan. 6, 2019 entitled “Smallmolecules as Inhibitors of HpHtRA protein in Helicobacter pylori”; U.S.Provisional Patent Application No. 62/788,953 filed Jan. 7, 2019entitled “CagA inhibitors associated with the H. pylori and/or gastriccancer”, all of which are incorporated by reference herein in theirentirety.

BACKGROUND

Some antibacterial compounds produced by human microbiota are involvedin different biological functions associated with human health and/ordisease conditions. Among the most common antibacterial compounds caninclude lantibiotics, bacteriocins and microcins.

Bacteriocins and lantibiotics are antimicrobial peptides or proteins(between 20 and 60 amino acids) synthesized by bacteria that inhibit orkill other microorganisms. Antibacterial compounds can promote abactericidal or bacteriostatic effect, inhibiting cell growth.Bacteriocins have been mainly used as safe food preservatives becausethey are easily digested by the human gastrointestinal tract. However,some bacteriocins and lantibiotics are used in health relatedapplications. Subtilosin A from Bacillus subtilis show anti-viral andspermicidal activities. Nisin, which is produced by some Gram-positivebacteria including Lactococcus and Streptococcus species, has theability to control many Gram-positive pathogens, such as Streptococcuspneumoniae, Enterococci and Clostridium difficile. Microcins are smallpeptides (less than 10 kDa) derived exclusively from Enterobacteriaceaeand have a potent antibacterial activity against close-related bacteriathat produce it. The action of microcin B17 on sensitive Escherichiacoli cells leads to the arrest of DNA replication and, consequently, tothe induction of the SOS response. Diverse applications of antibacterialcompounds are studied because some of them are recognized as GenerallyRecognized as Safe (GRAS) compounds by the FDA.

Examples of the use of bacteriocins include:

-   -   Salivaricin A, a bacteriocin producing by Streptococcus        salivarius K12 has been studied to inhibit malodour-associated        bacterial species such as Streptococcus anginosis T29,        Eubacterium saburreum and Micromonas micros.    -   Ruminococcin A, produced by Ruminococcus gnavus and Clostridium        nexile has been studied against C. perfringens and C. difficile,        suggesting as therapeutic agent against these pathogens. These        pathogens are associated to antibiotic associated diarrhoea, and        sporadic diarrhoea in humans.    -   Bacteriocin staphylococcus 188 has been studied against        Newcastle disease virus, influenza virus.

It has been described that the mucosal epithelia is used by severalmicroorganisms to adhere, internalize and/or take advantage of the hostproperties consequently producing diseases. As an example, one of themost targeted proteins is e-cadherin, a cell adhesion and tumorsuppressor protein that has a key role in the prevention of cancer. Asan example, microorganisms such as Escherichia coli, Shigella flexneri,Campylobacter jejuni and Helicobacter pylori express HtrA virulencefactors, that trigger cleavage of an extracellular section ofe-cadherin. E-cadherin cleavage leads to weaker cell-cell adhesion,which allow microorganisms to enter the intracellular epithelial spaceand provoke diseases, from diarrhea until cancer. Other microorganisms,such as Listeria monocytogenes, can be responsible for diseases such asgastroenteritis, meningoencephalitis and/or sepsis, produce cell wallinternalins to bind e-cadherin and promote internalization into hostcells. Thus, virulence factors that can bind e-cadherin are promisingdrug targets.

Gut microbiota includes a reservoir of microbes that are separated fromthe rest of the human system by intestinal epithelium. However, someconditions or diseases, such as intestine bowel disease (IBD),antibiotics use, aging, and/or other suitable conditions and/ordiseases, etc., might provoke the intestinal mucosal barrier to becomepermeable to molecules produced by microbiota, in a phenomenon known as“leaky gut” or “permeable intestine”.

The molecular mimicry mechanism is one of several mechanisms (e.g.,apart from the genetic predisposition), that can lead to autoimmunity.In that regard, bacteria can generate peptides that have a similarsequence than self peptides (e.g., molecular mimicry) and in a leaky gutenvironment, those peptides can be put into contact with T-cells and/orB-cells. In this way, T-cells and/or B-cells can cross react with thehost epitopes, leading to autoimmunity. This phenomenon is possiblebecause MHC class II molecules could be expressed on intestinal luminalcells, and those cells can process luminal peptides and present them toT-cells. Thus, bacterial peptides can lead to generate antibodies thatcan react against human proteins, causing the inhibition of thoseproteins functions. This generation of antibodies may eventually provokeand/or worsen metabolic, inflammatory and/or autoimmune diseases.

Some studies in mice have suggested that in genetically predisposedmice, the introduction of a gut microbiota species can triggerarthritis. Also, studies have shown that microbiota can participate intriggering other autoimmune diseases, such as Crohn's, Lupus, RheumatoidArthritis, and/or Psoriasis.

Helicobacter pylori has been classified as a class-I carcinogenresponsible of gastric cancer by the World Health Organization. H.pylori is able to colonize gastric epithelial of host cells, alteringgastric mucosa and provoking several inflammatory conditions, such asulcers, chronic gastritis, and/or gastric cancer. Moreover, H. pylorihas become resistant to antibiotics during the last decades.

One common target used by microorganisms for host cell attachment andinvasion is through E-cadherin. In gastric epithelial cells, E-cadherinplays a key role in maintaining cell junctions, preventing bacterialinvasions, and/or preventing cancer cell proliferation. E-cadherin canbe described as a single transmembrane protein which has fiveextracellular domain, an intracellular domain and a transmembranedomain.

HtrA is a heat shock induced serine protease with homologs in severalbacteria and eukaryotes. HtrA usually contributes to proteolyticdegradation of abnormal proteins. HtrA proteins share commonarchitecture such a proteolytic domain and a C-terminal PDZ domaininvolved in the binding of substrates. In H.pylori, HtrA has been shownto cleave the ectodomain of E-cadherin. Also, HtrA in othermicroorganisms such as Campylobacter jejuni is involved in bacterialinvasion and cleavage of E-cadherin. Both C. jejuni and H. pyloriactively secrete HtrA proteins to the extracellular environment, wherethey target host cell factors. Recently, the motif from E-cadherincleaved by HtrA can be described as ([VITA]-[VITA]-x-x-D-[DN]).

Sequence alignments of several HtrA proteins have shown a conservedchymotrypsinlike proteolytic domain, including three important residues:HIS 116, ASP 147, and SER 221. HtrA proteins have shown some advantagesas a target of drugs, for example including one or more of:

It is secreted towards the extracellular milieu or at the bacterialsurface, which can then enable it to be accessible to drugs;

The enzymatic active site can be characterized and described;

Host factors targeted by HtrA proteins, such as E-cadherin,proteoglycans and fibronectin, have important functions in bacterialpathogenesis.

Deletion of htrA gene in bacteria has been found to be lethal. Selectiveinhibition of HtrA proteins may help antibiotic treatment by preventingbacterial access to gastrointestinal tissues

Gastric Cancer (GC) is the fifth most common cancer in the world(incidence 5.7% of all cancers), and the third leading cause of cancerdeaths (8.2%), according with Global Cancer Observatory(http://gco.iarc.fr).

Additionally, Helicobacter pylori have been labeled as responsible fornearly 90% of the world's burden of noncardia gastric cancer, and it isthe most relevant infectious agent associated with gastric cancer. Atthe same time, multiple secondary effects have been associated withgastric cancer and H. pylori, as B12 and iron deficiency, due to badintestinal absorption, preeclampsia and also, due to failure in theeffect of therapeutic drugs.

H. pylori Infection Mechanisms:

Multiple metabolic pathways from H.pylori have been associated togastric cancer through gastric damage, those pathways include urease andinvasive virulence proteins, such as cytotoxin-associated gene A (CagA),Binding Adhesin A (BabA), sialic acid-binding adhesin (SabA),Vacuolating cytotoxin A (VacA), outer inflammatory protein A (OipA).Particularly, CagA is a virulence factor protein described as one of themajor inducer of GC, due to their capability to interact with multiplehuman proteins include of 3 domains well formed (I, II, III), apathogenicity domain (EPIYA motif) and a C-terminal multimerizationdomain (CM). CagA pathogenicity compromise multiple cellular responsesof the cell as motility, proliferation, mitosis, polarity, andjunctions. Particularly the CM domain, have been associated particularlywith an interaction with epithelial cadherin (e-cadherin), disruptingthe Wnt pathway and junction proteins, one of the main paths associatedwith GC. The junctions proteins have been relevant due to their rol overthe cohesion of the epithelium, regulating the cell morphology andrearrangement of the cellular cytoskeleton, and as such can includeimplications over several cancer types. Therefore, epithelial Cadherin(E-cadherin) is one of the most important proteins in mediatingcommunication between cells, acting like an indicator of growth andproliferation chances for the cell, or growth by an intracellular way.

Under normal situations, E-cadherin binds with β-catenin as a normalpart of Wnt signaling cascade (which is inactive). However, in gastriccancer, CagA binds and interact with E-cadherin which competes withβ-catenin binding processes, which promote the accumulation ofβ-catenin, and which can promote the transcription of multiple factorsinvolved in signaling of cellular proliferation, including possibleoncogenic genes.

BRIEF SUMMARY OF THE DISCLOSURE

The bacterial chaperone and serine protease-high temperature requirementA (HtrA)—is closely associated with the establishment and progression ofseveral infectious diseases. The present disclosure relates to one ormore HtrA inhibitors. Such inhibitors can be used as anti-infectiousagents. For example, an HtrA inhibitor can comprise Formula (I):

-   -   wherein:    -   R₁ is H, halo, cyano, OH, (C₁-C₆)alkyl, (C₃-C₁₀)heterocyclo,        (C₃-C₁₀)cycloalkyl, aryl, or heteroaryl, any of which may be        optionally substituted with 1 or more R^(w) groups as allowed by        valence selected from the groups listed in Table 1;    -   R₂ is H, halo, cyano, OH, (C₁-C₆)alkyl, (C₂-C₈)alkenyl,        (C₁-C₆)alkoxy, (C₃-C₁₀)heterocyclo, (C₃-C₁₀)cycloalkyl, aryl, or        heteroaryl, any of which may be optionally substituted with 1 or        more R^(w) groups as allowed by valence;    -   R₃ is H, halo, cyano, OH, (C₁-C₆)alkyl, (C₂-C₈)alkenyl,        (C₂-C₈)carboxyalkyl; N—(C₁-C₆)alkylaminocarbonyl, (C₁-C₆)alkoxy,        (C₁-C₆)sulfonyl, (C₃-C₁₀)heterocyclo, (C₃-C₁₀)cycloalkyl, aryl,        or heteroaryl, any of which may be optionally substituted with 1        or more R^(w) groups as allowed by valence;    -   R₄ is H, halo, cyano, OH, (C₁-C₆)alkyl, (C₂-C₈)alkenyl,        (C₂-C₈)carboxyalkyl; N—(C₁-C₆)alkylaminocarbonyl, (C₁-C₆)alkoxy,        (C₁-C₆)sulfonyl, (C₃-C₁₀)heterocyclo, (C₃-C₁₀)cycloalkyl, aryl,        or heteroaryl, any of which may be optionally substituted with 1        or more R^(w) groups as allowed by valence;    -   R₅ is H, halo, cyano, OH, (C₁-C₆)alkyl, (C₂-C₈)alkenyl,        (C₂-C₈)carboxyalkyl; N—(C₁-C₆)alkylaminocarbonyl, (C₁-C₆)alkoxy,        (C₁-C₆)sulfonyl, (C₃-C₁₀)heterocyclo, (C₃-C₁₀)cycloalkyl, aryl,        or heteroaryl, any of which may be optionally substituted with 1        or more R^(w) groups as allowed by valence;    -   R₆ is H, halo, cyano, OH, (C₁-C₆)alkyl, (C₂-C₈)alkenyl,        (C₂-C₈)carboxyalkyl; N—(C₁-C₆)alkylaminocarbonyl, (C₁-C₆)alkoxy,        (C₁-C₆)sulfonyl, (C₃-C₁₀)heterocyclo, (C₃-C₁₀)cycloalkyl, aryl,        or heteroaryl, any of which may be optionally substituted with 1        or more R^(w) groups as allowed by valence;

R^(w) at each occurrence is independently H, halo, cyano, nitro, oxo,amino, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkyl, wherein said alkyl, haloalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl,heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkyl groups may be further independently substituted withone or more groups selected from the group consisting of halo, cyano,oxo(C₃-C₁₀)heterocyclo, (C₃-C₁₀)cycloalkyl, —(CH₂)_(n)—(C₃-C₁₀)cycloalkyl, —(CH₂)_(n)—(C₃-C₁₀)heterocyclo, —(CH₂)_(n)-aryl,—(CH₂)_(n)-heteroaryl, aryl, and heteroaryl, wherein n is 0, 1, 2, 3, 4,5, or 6.

In an embodiment, the HtrA inhibitor is selected from the groupconsisting of:

-   N′-benzyl-N-[2-[(2R)-1-(4-methylphenyl)sulfonylpiperidin-2-yl]ethyl]oxamide;    1-[2-[methyl(naphthalen-2-ylsulfonyl)amino]acetyl]piperidine-4-carboxamide;    8-(4-methylphenyl)sulfonyl-4-(2,4,6-trimethylphenyl)sulfonyl-1-oxa-4,8-diazaspiro[4.5]decane;-   N-{1-[2-(2-Biphenylyloxy)ethyl]-3-pyrrolidinyl}-3,4-difluorobenzenesulfonamide;    1-(2-Anthrylsulfonyl)-3-piperidinecarboxylic acid;    (3S)-1-Carbamimidoyl-N-({(2S)-1-[N-(2-naphthylsulfonyl)glycyl]-2-pyrrolidinyl}methyl)-3-piperidinecarboxamide;-   (3S)-1-Carbamimidoyl-N-({(2S)-1-[N-(2-naphthylsulfonyl)-L-alanyl]-2-pyrrolidinyl}methyl)-3-piperidinecarboxamide;-   cyclohexyl[4-(1-naphthylsulfonyl)-2-(trifluoromethyl)-1-piperazinyl]methanone;    and    2-[(8S,11R)-11-((1R)-1-hydroxy-2-[(3-methylbutyl)(phenylsulfonyl)amino]ethyl)-6,9-dioxo-2-oxa-7,10-diazabicyclo[11.2.2]heptadeca-1(15),13,16-trien-8-yl]acetamide.

The present application also relates to a method of treating a bacterialinfection comprising administering a pharmaceutically effective amountof any one or more of the HtrA inhibitor described herein to a humansubject in need thereof. In an embodiment, the bacterial infection is aHelicobacter pylori infection.

The present disclosure also relates to a peptide of inhibiting CagA, aH. pylori virulence factor. Such peptides can be used as a therapeuticagent against the CagA mediated gastric cancer. In an embodiment, apeptide of inhibiting CagA has the sequence ofX₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂; wherein:

-   -   X₁ is D, R, H, I, F, P, W, or Y;    -   X₂ is T or N;    -   X₃ is D, N, or Y;    -   X₄ is P, E, L, or Y;    -   X₅ is T, R, or L;    -   X₆ is A or S;    -   X₇ is P, R, E, I, or L;    -   X₈ is P, I, L, or W;    -   X₉ is F, or Y;    -   X₁₀ is D, F, or W;    -   X₁₁ is S, A, D, E, H, I, L, or Y; and    -   X₁₂ is L, A, N, W, or Y.

In some embodiments, a peptide of inhibiting CagA has the sequence ofRTDPTAPPYDSL or DTDPTAPPYDSL.

The present discloser also relates to a method of treating gastriccancer comprising administering a pharmaceutically effective amount ofthe peptide described herein to a human subject in need thereof. Suchpeptides include, for example, DTDPTAPPYDSL and RTDPTAPPYDSL.

In another aspect, the present disclosure relates to a method ofinhibiting, down-regulating, reducing and/or killing pathogenic bacteriacomprising steps of: screening a microorganism that produces anantibacterial compound; conducting structural analysis of theantibacterial compound; and modifying the antibacterial compound toimprove the affinity to target bacteria.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically illustrates a method and/or system to detect newantibacterial compounds produced by microbiota bacteria.

FIG. 2 schematically illustrates a method and/or system to to modify theantibacterial compounds.

FIG. 3 schematically illustrates a method and/or system to detect newbacterial virulence factors that alter cell junctions.

FIG. 4 schematically illustrates a method and/or system to generatepeptide inhibitors against virulence factors, using the specific exampleof e-cadherin as cell-junction protein.

FIG. 5 schematically illustrates a method and/or system to findcandidate bacterial proteins, peptides, and/or other suitable componentsthat can trigger autoimmune response.

FIG. 6 illustrates Ro60 antigen orthologue protein found in Bacteroidesthetaiotaomicron associated with lupus, including the MHC-class IIbinding zone and the RNA zone.

FIG. 7 illustrates homology model of trimeric HtrA from Helicobacterpylori (left), and catalytic site of the protease, depicting residuesHIS 116, ASP 147 and SER 221 (right).

FIG. 8 illustrates specific examples of selected candidate moleculeswith docking energy of binding >−9.5 kcal/mol against HtrA receptor.

FIG. 9. Illustrates specific examples of selected candidate moleculeswith docking energy of binding >−8.9 kcal/mol against HtrA receptor.

FIG. 10. Illustrates specific examples of selected candidate moleculeswith docking energy of binding >−8.9 kcal/mol against HtrA receptor.

FIG. 11 illustrates the estimated deaths of cancer patients by type.

FIG. 12 illustrates the number of estimated cancers caused by thebacteria infection.

DETAILED DESCRIPTION OF THE DISCLOSURE Definition

The articles “a” and “an” as used herein and in the appended claims areused herein to refer to one or to more than one (i.e., to at least one)of the grammatical object of the article unless the context clearlyindicates otherwise. By way of example, “an element” means one elementor more than one element.

“

” indicates the double bond in E or Z configuration.

The term “H” denotes a single hydrogen atom. This radical may beattached, for example, to an oxygen atom to form a hydroxyl radical.

Where the term “alkyl” is used, either alone or within other terms suchas “haloalkyl” or “alkylamino”, it embraces linear or branched radicalshaving one to about twelve carbon atoms. More preferred alkyl radicalsare “lower alkyl” radicals having one to about six carbon atoms.Examples of such radicals include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and thelike. Even more preferred are lower alkyl radicals having one or twocarbon atoms. The term “alkylenyl” or “alkylene” embraces bridgingdivalent alkyl radicals such as methylenyl or ethylenyl. The term “loweralkyl substituted with R²” does not include an acetal moiety. The term“alkyl” further includes alkyl radicals wherein one or more carbon atomsin the chain is substituted with a heteroatom selected from oxygen,nitrogen, or sulfur.

The term “alkenyl” embraces linear or branched radicals having at leastone carbon-carbon double bond of two to about twelve carbon atoms. Morepreferred alkenyl radicals are “lower alkenyl” radicals having two toabout six carbon atoms. Most preferred lower alkenyl radicals areradicals having two to about four carbon atoms. Examples of alkenylradicals include ethenyl, propenyl, allyl, propenyl, butenyl and4-methylbutenyl. The terms “alkenyl” and “lower alkenyl”, embraceradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations.

The term “alkynyl” denotes linear or branched radicals having at leastone carbon-carbon triple bond and having two to about twelve carbonatoms. More preferred alkynyl radicals are “lower alkynyl” radicalshaving two to about six carbon atoms. Most preferred are lower alkynylradicals having two to about four carbon atoms. Examples of suchradicals include propargyl, and butynyl, and the like.

Alkyl, alkylenyl, alkenyl, and alkynyl radicals may be optionallysubstituted with one or more functional groups such as halo, hydroxy,nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocyclo andthe like.

The term “halo” means halogens such as fluorine, chlorine, bromine oriodine atoms.

The term “haloalkyl” embraces radicals wherein any one or more of thealkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkylradicals including perhaloalkyl. A monohaloalkyl radical, for example,may have either an iodo, bromo, chloro or fluoro atom within theradical. Dihalo and polyhaloalkyl radicals may have two or more of thesame halo atoms or a combination of different halo radicals. “Lowerhaloalkyl” embraces radicals having 1 to 6 carbon atoms. Even morepreferred are lower haloalkyl radicals having one to three carbon atoms.Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl.

The term “perfluoroalkyl” means alkyl radicals having all hydrogen atomsreplaced with fluoro atoms. Examples include trifluoromethyl andpentafluoroethyl.

The term “hydroxyalkyl” embraces linear or branched alkyl radicalshaving one to about ten carbon atoms any one of which may be substitutedwith one or more hydroxyl radicals. More preferred hydroxyalkyl radicalsare “lower hydroxyalkyl” radicals having one to six carbon atoms and oneor more hydroxyl radicals. Examples of such radicals includehydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl andhydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals havingone to three carbon atoms.

The term “alkoxy” embraces linear or branched oxy-containing radicalseach having alkyl portions of one to about ten carbon atoms. Morepreferred alkoxy radicals are “lower alkoxy” radicals having one to sixcarbon atoms. Examples of such radicals include methoxy, ethoxy,propoxy, butoxy and tert-butoxy. Even more preferred are lower alkoxyradicals having one to three carbon atoms. Alkoxy radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkoxy” radicals. Even more preferred arelower haloalkoxy radicals having one to three carbon atoms. Examples ofsuch radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,trifluoroethoxy, fluoroethoxy and fluoropropoxy.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one or two rings, wherein such rings may be attachedtogether in a fused manner. The term “aryl” embraces aromatic radicalssuch as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and indanyl. Morepreferred aryl is phenyl. An “aryl” group may have 1 or moresubstituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro,cyano, alkoxy, and lower alkylamino, and the like. Phenyl substitutedwith —O—CH₂—O— forms the aryl benzodioxolyl substituent.

The term “heterocyclyl” (or “heterocyclo”) embraces saturated, partiallysaturated and unsaturated heteroatom-containing ring radicals, where theheteroatoms may be selected from nitrogen, sulfur and oxygen. It doesnot include rings containing —O—O—,—O—S— or —S—S— portions. The“heterocyclyl” group may have 1 to 4 substituents such as hydroxyl, Boc,halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy,amino and lower alkylamino.

Examples of saturated heterocyclic radicals include saturated 3 to6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms[e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,piperazinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.,morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl anddihydrothiazolyl.

Examples of unsaturated heterocyclic radicals, also termed “heteroaryl”radicals, include unsaturated 5 to 6 membered heteromonocyclyl groupcontaining 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl,pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic groupcontaining an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.;unsaturated 5 to 6-membered heteromonocyclic group containing a sulfuratom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl[e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl];unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl].

The term heterocyclyl, (or heterocyclo) also embraces radicals whereheterocyclic radicals are fused/condensed with aryl radicals:unsaturated condensed heterocyclic group containing 1 to 5 nitrogenatoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl[e.g., tetrazolo [1,5-b]pyridazinyl]; unsaturated condensed heterocyclicgroup containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturatedand unsaturated condensed heterocyclic group containing 1 to 2 oxygen orsulfur atoms [e.g. benzofuryl, benzothienyl,2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Preferredheterocyclic radicals include five to ten membered fused or unfusedradicals. More preferred examples of heteroaryl radicals includequinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl,oxazolyl, furyl and pyrazinyl. Other preferred heteroaryl radicals are5- or 6-membered heteroaryl, containing one or two heteroatoms selectedfrom sulfur, nitrogen and oxygen, selected from thienyl, furyl,pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl.

Particular examples of non-nitrogen containing heteroaryl includepyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuryl, andbenzothienyl, and the like.

Particular examples of partially saturated and saturated heterocyclylinclude pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

The term “heterocyclo” thus encompasses the following ring systems:

and the like.

The term “sulfonyl”, whether used alone or linked to other terms such asalkylsulfonyl, denotes respectively divalent radicals —SO₂—.

The terms “sulfamyl,” “aminosulfonyl” and “sulfonamidyl,” denotes asulfonyl radical substituted with an amine radical, forming asulfonamide (—SO₂NH₂).

The term “alkylaminosulfonyl” includes “N-alkylaminosulfonyl” wheresulfamyl radicals are independently substituted with one or two alkylradical(s). More preferred alkylaminosulfonyl radicals are “loweralkylaminosulfonyl” radicals having one to six carbon atoms. Even morepreferred are lower alkylaminosulfonyl radicals having one to threecarbon atoms. Examples of such lower alkylaminosulfonyl radicals includeN-methylaminosulfonyl, and N-ethylaminosulfonyl.

The terms “carboxy” or “carboxyl,” whether used alone or with otherterms, such as “carboxyalkyl,” denotes —CO₂H.

The term “carbonyl,” whether used alone or with other terms, such as“aminocarbonyl,” denotes —(C═O)—.

The term “aminocarbonyl” denotes an amide group of the formula C(═O)NH₂.

The terms “N-alkylaminocarbonyl” and “N,N-dialkylaminocarbonyl” denoteaminocarbonyl radicals independently substituted with one or two alkylradicals, respectively. More preferred are “lower alkylaminocarbonyl”having lower alkyl radicals as described above attached to anaminocarbonyl radical.

The terms “N-arylaminocarbonyl” and “N-alkyl-N-arylaminocarbonyl” denoteaminocarbonyl radicals substituted, respectively, with one aryl radical,or one alkyl and one aryl radical.

The terms “heterocyclylalkylenyl” and “heterocyclylalkyl” embraceheterocyclic-substituted alkyl radicals. More preferredheterocyclylalkyl radicals are “5- or 6-membered heteroarylalkyl”radicals having alkyl portions of one to six carbon atoms and a 5- or6-membered heteroaryl radical. Even more preferred are lowerheteroarylalkylenyl radicals having alkyl portions of one to threecarbon atoms. Examples include such radicals as pyridylmethyl andthienylmethyl.

The term “aralkyl” embraces aryl-substituted alkyl radicals. Preferablearalkyl radicals are “lower aralkyl” radicals having aryl radicalsattached to alkyl radicals having one to six carbon atoms. Even morepreferred are “phenylalkylenyl” attached to alkyl portions having one tothree carbon atoms. Examples of such radicals include benzyl,diphenylmethyl and phenylethyl. The aryl in said aralkyl may beadditionally substituted with halo, alkyl, alkoxy, halkoalkyl andhaloalkoxy.

The term “alkylthio” embraces radicals containing a linear or branchedalkyl radical, of one to ten carbon atoms, attached to a divalent sulfuratom. Even more preferred are lower alkylthio radicals having one tothree carbon atoms. An example of “alkylthio” is methylthio, (CH₃S—).

The term “haloalkylthio” embraces radicals containing a haloalkylradical, of one to ten carbon atoms, attached to a divalent sulfur atom.Even more preferred are lower haloalkylthio radicals having one to threecarbon atoms. An example of “haloalkylthio” is trifluoromethylthio.

The term “alkylamino” embraces “N-alkylamino” and “N,N-dialkylamino”where amino groups are independently substituted with one alkyl radicaland with two alkyl radicals, respectively. More preferred alkylaminoradicals are “lower alkylamino” radicals having one or two alkylradicals of one to six carbon atoms, attached to a nitrogen atom. Evenmore preferred are lower alkylamino radicals having one to three carbonatoms. Suitable alkylamino radicals may be mono or dialkylamino such asN-methylamino, N-ethylamino, N,N-dimethylamino, and N,N-diethylamino,and the like.

The term “arylamino” denotes amino groups, which have been substitutedwith one or two aryl radicals, such as N-phenylamino. The arylaminoradicals may be further substituted on the aryl ring portion of theradical.

The term “heteroarylamino” denotes amino groups, which have beensubstituted with one or two heteroaryl radicals, such as N-thienylamino.The “heteroarylamino” radicals may be further substituted on theheteroaryl ring portion of the radical.

The term “aralkylamino” denotes amino groups, which have beensubstituted with one or two aralkyl radicals. More preferred arephenyl-C₁-C₃-alkylamino radicals, such as N-benzylamino. Thearalkylamino radicals may be further substituted on the aryl ringportion.

The terms “N-alkyl-N-arylamino” and “N-aralkyl-N-alkylamino” denoteamino groups, which have been independently substituted with one aralkyland one alkyl radical, or one aryl and one alkyl radical, respectively,to an amino group.

The term “aminoalkyl” embraces linear or branched alkyl radicals havingone to about ten carbon atoms any one of which may be substituted withone or more amino radicals. More preferred aminoalkyl radicals are“lower aminoalkyl” radicals having one to six carbon atoms and one ormore amino radicals. Examples of such radicals include aminomethyl,aminoethyl, aminopropyl, aminobutyl and aminohexyl. Even more preferredare lower aminoalkyl radicals having one to three carbon atoms.

The term “alkylaminoalkyl” embraces alkyl radicals substituted withalkylamino radicals. More preferred alkylaminoalkyl radicals are “loweralkylaminoalkyl” radicals having alkyl radicals of one to six carbonatoms. Even more preferred are lower alkylaminoalkyl radicals havingalkyl radicals of one to three carbon atoms. Suitable alkylaminoalkylradicals may be mono or dialkyl substituted, such asN-methylaminomethyl, N,N-dimethyl-aminoethyl, andN,N-diethylaminomethyl, and the like.

The term “alkylaminoalkoxy” embraces alkoxy radicals substituted withalkylamino radicals. More preferred alkylaminoalkoxy radicals are “loweralkylaminoalkoxy” radicals having alkoxy radicals of one to six carbonatoms. Even more preferred are lower alkylaminoalkoxy radicals havingalkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxyradicals may be mono or dialkyl substituted, such asN-methylaminoethoxy, N,N-dimethylaminoethoxy, andN,N-diethylaminoethoxy, and the like.

The term “alkylaminoalkoxyalkoxy” embraces alkoxy radicals substitutedwith alkylaminoalkoxy radicals. More preferred alkylaminoalkoxyalkoxyradicals are “lower alkylaminoalkoxyalkoxy” radicals having alkoxyradicals of one to six carbon atoms. Even more preferred are loweralkylaminoalkoxyalkoxy radicals having alkyl radicals of one to threecarbon atoms. Suitable alkylaminoalkoxyalkoxy radicals may be mono ordialkyl substituted, such as N-methylaminomethoxyethoxy,N-methylaminoethoxyethoxy, N,N-dimethylaminoethoxyethoxy, andN,N-diethylaminomethoxymethoxy, and the like.

The term “carboxyalkyl” embraces linear or branched alkyl radicalshaving one to about ten carbon atoms any one of which may be substitutedwith one or more carboxy radicals. More preferred carboxyalkyl radicalsare “lower carboxyalkyl” radicals having one to six carbon atoms and onecarboxy radical. Examples of such radicals include carboxymethyl, andcarboxypropyl, and the like. Even more preferred are lower carboxyalkylradicals having one to three CH₂ groups.

The term “halosulfonyl” embraces sulfonyl radicals substituted with ahalogen radical. Examples of such halosulfonyl radicals includechlorosulfonyl and fluorosulfonyl.

The term “arylthio” embraces aryl radicals of six to ten carbon atoms,attached to a divalent sulfur atom. An example of “arylthio” isphenylthio.

The term “aralkylthio” embraces aralkyl radicals as described above,attached to a divalent sulfur atom. More preferred arephenyl-C₁-C₃-alkylthio radicals. An example of “aralkylthio” isbenzylthio.

The term “aryloxy” embraces optionally substituted aryl radicals, asdefined above, attached to an oxygen atom. Examples of such radicalsinclude phenoxy.

The term “aralkoxy” embraces oxy-containing aralkyl radicals attachedthrough an oxygen atom to other radicals. More preferred aralkoxyradicals are “lower aralkoxy” radicals having optionally substitutedphenyl radicals attached to lower alkoxy radical as described above.

The term “heteroaryloxy” embraces optionally substituted heteroarylradicals, as defined above, attached to an oxygen atom.

The term “heteroarylalkoxy” embraces oxy-containing heteroarylalkylradicals attached through an oxygen atom to other radicals. Morepreferred heteroarylalkoxy radicals are “lower heteroarylalkoxy”radicals having optionally substituted heteroaryl radicals attached tolower alkoxy radical as described above.

The term “cycloalkyl” includes saturated carbocyclic groups. Preferredcycloalkyl groups include C₃-C₆ rings. More preferred compounds include,cyclopentyl, cyclopropyl, and cyclohexyl.

The term “cycloalkylalkyl” embraces cycloalkyl-substituted alkylradicals. Preferable cycloalkylalkyl radicals are “lowercycloalkylalkyl” radicals having cycloalkyl radicals attached to alkylradicals having one to six carbon atoms. Even more preferred are “5 to6-membered cycloalkylalkyl” attached to alkyl portions having one tothree carbon atoms. Examples of such radicals include cyclohexylmethyl.The cycloalkyl in said radicals may be additionally substituted withhalo, alkyl, alkoxy and hydroxy.

The term “cycloalkenyl” includes carbocyclic groups having one or morecarbon-carbon double bonds including “cycloalkyldienyl” compounds.Preferred cycloalkenyl groups include C₃-C₆ rings. More preferredcompounds include, for example, cyclopentenyl, cyclopentadienyl,cyclohexenyl and cycloheptadienyl.

The term “comprising” is meant to be open ended, including the indicatedcomponent but not excluding other elements.

A group or atom that replaces a hydrogen atom is also called asubstituent.

Any particular molecule or group can have one or more substituentdepending on the number of hydrogen atoms that can be replaced.

The symbol “-” represents a covalent bond and can also be used in aradical group to indicate the point of attachment to another group. Inchemical structures, the symbol is commonly used to represent a methylgroup in a molecule.

The term “therapeutically effective amount” means an amount of acompound that ameliorates, attenuates or eliminates one or more symptomof a particular disease or condition, or prevents or delays the onset ofone of more symptom of a particular disease or condition.

The terms “patient” and “subject” may be used interchangeably and meananimals, such as dogs, cats, cows, horses, sheep and humans. Particularpatients are mammals. The term patient includes males and females.

The term “pharmaceutically acceptable” means that the referencedsubstance, such as a compound of Formula I, or a salt of a compound ofFormula I, or a formulation containing a compound of Formula I, or aparticular excipient, are suitable for administration to a patient.

The terms “treating”, “treat” or “treatment” and the like includepreventative (e.g., prophylactic) and palliative treatment.

The term “excipient” means any pharmaceutically acceptable additive,carrier, diluent, adjuvant, or other ingredient, other than the activepharmaceutical ingredient (API), which is typically included forformulation and/or administration to a patient.

The term “cancer” means a physiological condition in mammals that ischaracterized by unregulated cell growth. General classes of cancersinclude carcinomas, lymphomas, sarcomas, and blastomas.

The following description of the embodiments is not intended to limitthe embodiments, but rather to enable any person skilled in the art tomake and use.

In embodiments, methods (e.g., pipeline, etc.) and/or systems (e.g.,components facilitating performance of the pipeline; therapeuticcompositions etc.) (and/or suitable portions of the embodiments) caninclude and/or function to inhibit, down-regulate, reduce and/or killpathogenic bacteria using antibacterial compounds from the microbiota.In embodiments, the methods and/or systems can use one or morebioinformatics pipelines to identify compounds in the microbiota and/orcan use one or more structural biology techniques to design newantibacterial compounds, such as by using as a basis the existing ones.In examples, the obtained antibacterial compounds can be used astreatment of one or more diseases and/or conditions, such as forhealthcare, biotechnology, and pharmaceutical applications. In examples,other uses of these antibacterial compounds can additionally oralternatively include one or more of: food preservation, producingactive probiotic culture, treatment of infections, antibiotic resistanceto conventional antibiotics, post-surgical control of infectiousbacteria, anti-cancer agents, and/or other suitable uses.

In embodiments, the method (e.g., pipeline, etc.) and/or system caninclude a first stage (and/or can be performed at any suitable time andfrequency), which can include finding new antibacterial compoundsproduced by the microbiota. In examples, in this stage (and/or at anysuitable time and frequency), a screening of known antibacterialcompounds-producing microorganisms and/or antibacterial compounds can beperformed, such as to generate one or more databases of antibacterialcompounds produced by bacteria and/or other suitable microorganisms. Inexamples, all related information can be determined and/or stored (e.g.,data usable for subsequent steps, etc.), such as including one or moreof: the name of the antibacterial, the microorganisms that produce it,the application, host site, target microorganisms that inhibit and/orkill, and/or any other suitable data. In examples, curated antibacterialcompounds (e.g., lantibiotic, bacteriocin, microcin, etc.), such asstored in the database, can be search against reference proteomes (e.g.,from Uniprot or NCBI databases, etc.) using one or more sequencealignment algorithms (e.g., BLAST, FASTA, Clustal, among others, etc.).In examples, the alignment(s) can be used to identify peptide motif(s)that can be useful to predict the binding region of antibacterialcompounds to other microorganisms, and/or to identify newbacteria-producing antibacterial compounds (e.g., an example of thisstage is depicted in FIG. 1).

In embodiments, the method (e.g., pipeline, etc.) and/or system caninclude second stage (and/or can be performed at any suitable time andfrequency) which can include and/or function to allow modification ofthe antibacterial compounds to improve the antimicrobial activity. Inexamples, the method and/or system can include modifying antibacterialpeptides that have a defined tridimensional structure and/or have aknown particular target (e.g., obtained from a structural database, suchas Protein Data Bank, Bactibase, BAGEL, among others, etc.). Inexamples, according to that, and/or based on the identification ofrelevant peptide motif(s) from the first stage (and/or at any suitabletime and frequency), a structural analysis can be performed to identifywhether those motifs are exposed to the solvent and, therefore, caninteract with proteins from other microorganisms. In examples, thisanalysis can be performed using solvent-accessible surface area (SASA)but can additionally or alternatively be otherwise performed. Inexamples, then, a molecular docking (e.g., as control) can be performedto model the atomic interaction between the antimicrobial peptide and/ormotif and the target from a microorganism(s) known to be inhibited bythe action of the antibacterial peptide. In examples, both molecules areconsidered rigid, that is, the bonds do not rotate and maintain thesecondary structure. In examples, taking this into account, newantimicrobial peptides can be designed. In examples, to do this,modifications on segments of amino acids of antibacterial peptide(s) canbe performed to determine and/or obtain new antibacterial peptide(s)with improved antimicrobial activity. The modifications can includemutating each position of peptides (and/or any suitable position) forone or more of the remaining 19 amino acids. In examples, subsequently,docking between modified peptides and the target can be performed. Inexamples, thus, the new antibacterial peptide can bind with highaffinity to the target, and therefore, can improve their antimicrobialactivity (e.g., an example of this procedure is shown in FIG. 2).

Embodiments can additionally or alternatively include applying anysuitable approaches described herein for identification, generation,application, provision, and/or other suitable usage (e.g., intherapeutic compositions, etc.) of any suitable peptides, proteins,and/or other components, such as for any suitable antimicrobialactivity, diseases, and/or conditions (e.g., described herein, etc.).

Embodiments of the method and/or system can additionally oralternatively include:

One or more methodologies to identify new antibacterial compounds (e.g.,peptides, proteins, etc.) produced by the human microbiota.

One or more methodologies to modify the antibacterial compounds (e.g.,peptides, proteins, etc.) to determine and/or obtain new ones.

Embodiments can additionally or alternatively include applying anysuitable approaches described herein for identification, generation,application, provision, and/or other suitable usage (e.g., intherapeutic compositions, etc.) of any suitable peptides, proteins,and/or other components, such as for any suitable antimicrobialactivity, diseases, and/or conditions (e.g., described herein, etc.).

In embodiments, methods (e.g., pipeline, etc.) and/or systems (e.g.,components facilitating performance of the pipeline; therapeuticcompositions etc.) (and/or suitable portions of the embodiments) canfunction to and/or include identification and/or targeting of virulencefactors in bacteria (and/or other suitable microorganisms) that bindhuman cell-junctions proteins (e.g., e-cadherin, etc.), such as newtargets of drugs that can help to prevent diseases and/or conditionsprovoked by those bacteria (and/or other suitable microorganisms), suchas one or more of: colorectal cancer, gastric cancer, pancreatic cancer,gallbladder cancer, chronic diarrhea, abdominal infections and/or othersuitable diseases and/or conditions. Additionally or alternatively,embodiments of the method and/or system can include the protection ofcell-junctions proteins from cleavage mediated by the binding ofbacterial virulence factors. In examples, the protection is addressedthrough the development of new peptide drugs. Additionally oralternatively, embodiments can include a pipeline and/or suitableapproaches, which allow identification of new virulence proteins thattarget cell-junctions proteins. In examples, by analyzing the bindinginterface between the proteins, new peptides that can target virulencefactor can be generated, aimed to prevent cell-junction protein bindingand/or cleavage. In examples, the method and/or system can includeand/or otherwise be used for new drugs that can prevent, ameliorate,and/or otherwise improve diseases provoked by adherens proteins frombacteria and/or other suitable microorganisms.

In embodiments, the method (e.g., pipeline) and/or system aims to findorthologous bacterial virulence factors to those already known bysequence matching against reference proteomes (e.g. available in NCBI).In examples, to this end, one or more alignment algorithms can be used(e.g., BLAST, FASTA, CLUSTAL, among others). Additionally oralternatively, structural information of known virulence factors (e.g.,as those available in the Protein Data Bank—PDB) and predicted bindingto a cell-junction protein (e.g e-cadherin) can be used to identifyprotein motifs in the binding site, allowing to identify new virulencefactors in available bacterial proteomes. In examples, sequencesimilarity networks can be used to classify different classes ofvirulence factors that bind cell-junction proteins (e.g., E-cadherin,etc.), depending on the mechanisms that the proteins use to disruptcell-junction proteins (e.g., E-cadherin, etc.).

In examples, new virulence factors that can alter cell junctions canadditionally or alternatively be identified. Additionally oralternatively, using the available structural information in thestructural databases (e.g., PDB, etc.), the binding site between thecell-junction protein (e.g., E-cadherin) and the different virulencefactors can be determined. In examples, if a specific virulence factoris not found, a homology model of the structure can be obtained and thebinding site can be found. In examples, once the binding site isdetermined, a peptide with higher affinity than the originalcell-junction protein-binding site can be obtained by in-silicoreengineering techniques (e.g., one or more of molecular docking,fragment-based discovery, free energy calculations, etc). In examples,thus, it is expected that new peptide drugs can bind with high affinityto the virulence factor, inhibiting by competition the original bindingwith the cell-junction protein.

However, any suitable portions, approaches, and/or steps described aboveand/or herein can be performed in any suitable sequence, and at anysuitable time and frequency.

Embodiments of the method and/or system can additionally oralternatively include:

One or more pipelines to identify new proteins, peptides, and/or othercomponents as virulence factors that can alter cell junctions, such asby cell-junction protein binding.

One or more pipelines to identify peptides, proteins, and/or othersuitable components as inhibitors of the cell-junction protein (e.g.,E-cadherin, etc.)/virulence factors binding.

Embodiments can additionally or alternatively include applying anysuitable approaches described herein for identification, generation,application, provision, and/or other suitable usage (e.g., intherapeutic compositions, etc.) of any suitable proteins, peptides,and/or other components for targeting cell junctions, such as for anysuitable conditions (e.g., described herein, etc.).

In embodiments, methods method (e.g., pipeline, etc.) and/or systems(e.g., components facilitating performance of the pipeline; therapeuticcompositions etc.) (and/or suitable portions of the embodiments)disclosed can function to identify one or more bacterial proteins,peptides, and/or other components, that can cause cross reaction withhuman proteins, peptides, and/or other components. Additionally oralternatively, embodiments can include one or more approaches to inhibitthe action of such bacterial proteins, peptides, and/or other components(e.g., for inhibiting the cross reaction with human proteins, peptides,and/or other components).

Embodiments of methods and/or systems (e.g., therapeutic compositions;etc.) can be identify bacterial proteins that can produce cross-reactionwith human ones and to target such bacterial proteins using smallmolecules or peptides. In embodiments, the methods can include aprocedure for identifying bacterial proteins that can lead tocross-reaction with host proteins. In examples, the obtained bacterialproteins are screened to find MHC class II epitopes, thus the proteinshaving those epitopes can be identified to generate antibody production.Additionally or alternatively, identified proteins can be new targetsfor the design of peptide inhibitors. In specific examples, newpeptide-based drugs to target cross-reactive proteins can be used toalleviate or prevent the triggering of autoimmune diseases.

In embodiments, the method (e.g., pipeline, etc.) and/or system caninclude a first step (and/or can be performed at any suitable time andfrequency), which can include one or more sequence identity searchesperformed between human gut microbiota reference proteomes (e.g.,Uniprot and/or NCBI, etc.) against the human proteome and/or othersuitable components. Any suitable combination of the organisms (e.g.,taxa, all organisms, etc.) detected and/or detectable in the human gut(e.g., by any suitable database) can be considered, but any suitabledatabase (e.g., Human Microbiome project, etc.) can additionally oralternatively be used. In a specific example, the similarity search isperformed by using a sequence alignment algorithm (e.g. pBLAST), but anysuitable similarity search approaches can additionally or alternativelybe used. In a specific example, bacterial protein regions that matchwith human proteins are saved.

In embodiments, the method and/or system can include a second stage(and/or can be performed at any suitable time and frequency), which caninclude bacterial proteins regions obtained in the first stage (and/orat any suitable time and frequency) being analyzed to find HLA-class IIepitopes. In specific examples, HLA-class II alleles are considereddepending on each health condition or disease. In specific examples,this can be performed by one or more tools (e.g., Propred, IEDB, etc).In specific examples, proteins and/or peptide fragments that werepredicted to have epitopes sequences can then be correlated withautoimmune diseases and/or conditions (e.g., by literature curation). Inspecific examples, cluster visualization can be performed to identifythe predominant taxonomic order of those bacteria predicted to haveproteins implied in a specific disease and/or condition.

In embodiments, the method and/or system can include a later stage(and/or can be performed at any suitable time and frequency), which caninclude generating peptide inhibitors targeting bacterial proteins. Inexamples, first, a structural model of the bacterial protein and/orepitope should be obtained from a structural database (e.g. Protein DataBank PDB, etc.). In examples, if the sequence is short, peptidemodelling can additionally or alternatively apply. In examples, if theprotein fragment is large, a homology model can be built. The receptor,MHC-class II molecule, can be obtained from the structural database(e.g., PDB, etc.) and/or modelled according to the allele associatedwith the health condition under study (e.g., lupus risk alleles areHLA-DR3 and HLA-DR15).

Embodiments of the method and/or system can additionally oralternatively include:

One or more methodologies to identify bacterial proteins, peptides,and/or other suitable components responsible for triggering anautoimmune reaction.

One or more methodologies to obtain inhibitory peptides, proteins,and/or other suitable components against bacterial proteins, peptides,and/or other suitable components that mediate autoimmune reactions.

Embodiments can additionally or alternatively include applying anysuitable approaches described herein for identification, generation,application, provision, and/or other suitable usage (e.g., intherapeutic compositions, etc.) of any suitable peptides, proteins,and/or other components, such as for any suitable autoimmune conditions(e.g., described herein, etc.).

Specific Examples

As an example, an inhibitory lead peptide can be obtained from thebacterial protein binding region in the MHC-class II receptor. Inexamples, by using in-silico reengineering aided by molecular docking,that means, by producing single or double mutations in the lead peptide,a peptide with higher affinity to bacterial protein than the originalMHC-class II binding site can be generated. Thus, in examples, it isexpected that the new peptide can inhibit by competition the bacterialprotein binding to MHC-class II receptor. In specific examples, someconsiderations can be taken into account, for example, the inhibitorypeptides should not cross-react with human proteins triggering otherautoimmune responses; to meet this requirement, inhibitory peptides canbe searched against proteins/peptides found in the first stage (and/orat any suitable time and frequency), which are candidates to beautoimmune protein candidates.

In an example, embodiments can include and/or otherwise be applied forthe targeting of Ro60 antigen orthologue bacterial protein. In humans,Ro60 protein has a RNA repair role (e.g., as shown in FIG. 2). However,in lupus disease patients, antibodies are generated against thisantigen. Moreover, this antigen has orthologs in the microbiota (inBacteroides thetaiotaomicron in gut), thus an increased immunityresponse (and excessive antibodies generation) is provoked. In thatregard, Ro60 from bacteria can produce a chronic stimulus. In a specificexample, one or more peptides, proteins, and/or other suitablecomponents that prevent MHC-II binding to Ro60 bacterial protein can bedesigned, generated, provided, applied, and/or otherwise used (e.g., ina therapeutic composition, etc.).

However, any suitable portions, approaches, and/or steps described aboveand/or herein can be performed in any suitable sequence, and at anysuitable time and frequency.

In embodiments, according to the mentioned antecedents, newpathogen-selective HtrA inhibitors might represent a new drug discoveryopportunity. In embodiments, the method and/or system can include and/orotherwise prevent E-cadherin cleavage mediated by HtrA proteins fromH.pylori. In embodiments, the method and/or system can include and/orotherwise identify and generate inhibitors of the proteolytic region ofHrtA proteins from H.pylori, aimed to prevent E-cadherin binding andcleavage. In embodiments, the method and/or system can include,determine, provide, generate, administer, and/or otherwise facilitatenew drugs, such as drugs that can be used to prevent attachment and/orcleavage mediated by H.pylori, thus they can be used as palliativeand/or as a treatment against gastric cancer and/or any other suitablegastrointestinal conditions, cancers, and/or other suitable conditions.

The crystal structure of H. pylori HtrA with a deletion of the PDZ2domain (PDB ID: 5Y28) with a resolution of 3.08 Å is obtainable, andadditional characteristics regarding this structure can additionally oralternatively be determined. In variations, the method and/or system caninclude and/or be used to generate one or more trimeric homologymodel(s) including PDZ2 domain (sequence UNIPROT ID: G2J5T2), such aswhere DegS protein from E. coli can be used as a template (PDB: 4RQY)but any suitable proteins and/or or microorganisms can be used fortemplates. In a specific example, the homologous region between bothproteins includes 37% sequence identity and 67% sequence similarity. Inexamples, the homology model and the crystal structure in PDB ID: 5Y28can be structurally aligned and the PDZ1 and the proteolytic domain arestructurally similar (RMSD). A potential allosteric site in each monomerof the trimer can act as a potential site (e.g., ideal site) for drugbinding, which can facilitate preventing pathogen transmigration acrossthe gastric epithelial barrier.

In examples, the method and/or system can include and/or be used toperform, after the HtrA homology model is built (and/or at any suitabletime and frequency), the control binding affinity of an in-silicoreported inhibitor was calculated as a reference through dockingsimulations. In a specific example, this binding energy was calculatedin −7.5 kcal/mol. Compounds can exist (K_(D)=13 μM and IC₅₀=26 μM),which according to our docking calculation has HtrA binding energy of−7.7 kcal/mol and −8.1 kcal/mol. Embodiments can include, In the searchof new possible inhibitors of HtrA proteolytic function, screening a setof molecules from a suitable source (e.g. CHEMBL database and/or anyother suitable databases and/or other suitable sources) against HtrAenzyme using massive molecular docking simulations (and/or othersuitable in silico approaches and/or other suitable approaches; etc.).In embodiments, the method and/or system can include applying anysuitable set of criteria (e.g., thresholds; etc.). In examples, fromthis set, only molecules with a Tanimoto similarity coefficient higherthan 0.5 compared with a reported inhibitor were considered; however,any suitable thresholds (e.g., any suitable Tanimoto similaritycoefficient value; etc.) and/or other suitable criteria for the Tanimotosimilarity coefficient, other similarity coefficients, and/or othersuitable metrics can be used. In examples, then, these molecules werefiltered by applying Lipinski rules of druggability (and/or any suitablecriteria). In specific examples, the Lipinski rules of druggability caninclude any one or more of: molecular weight <500 daltons, number ofH-bonds donor <5, number of H-bonds acceptor <10, number of N and Oatoms <15, range of partition coefficient log P between −2 and 5, numberof rotatable bonds <10, number of ring number <10; and/or any othersuitable criteria.

The present application also relates to a method of treating a bacterialinfection comprising administering a pharmaceutically effective amountof the HtrA inhibitor described herein to a human subject in needthereof. In an embodiment, the bacterial infection is a Helicobacterpylori infection.

The following includes a specific example of a main scaffold (Formula(I)):

wherein R₁ to R₆ are defined below and the dotted line indicates thebond is either none, a single bond or a double bond. For clarity, eachcell of Tables 1-6 illustrates the chemical structure of the substituenton the top and its Canonical SMILES at the bottom. “A” indicates eitherH or the connection position of the group. For example, “A-Cl” indicatesthat the substituent is —Cl; “A-” indicates that the substituent is—CH₃. If there are two or more “A” in the chemical structure, each A isindependently either H or the connection position.

R₁

R₁ can be H, halo, cyano, OH, (C₁-C₆)alkyl, (C₃-C₁₀)heterocyclo,(C₃-C₁₀)cycloalkyl, aryl, or heteroaryl, any of which may be optionallysubstituted with 1 or more R^(w) groups as allowed by valence; whereinR^(w) at each occurrence is independently H, halo, cyano, nitro, oxo,amino, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkyl, wherein said alkyl, haloalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl,heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, andheterocycloalkyl groups may be further independently substituted withone or more groups selected from the group consisting of halo, cyano,oxo(C₃-C₁₀)heterocyclo, (C₃-C₁₀)cycloalkyl, —(CH₂)_(n)—(C₃-C₁₀)cycloalkyl, —(CH₂)_(n)—(C₃-C₁₀)heterocyclo, —(CH₂)_(n)-aryl,—(CH₂)_(n)-heteroaryl, aryl, and heteroaryl, wherein n is 0, 1, 2, 3, 4,5, or 6.

In some embodiments, R₁ is selected from the groups listed in Table 1.

TABLE 1 R₁ substituent A—Cl Cl* A [*H]

FC(F)(F)*

C(CC(N(C)C)*)C* A—F F*

C(CC*)C* A— C*

C(NC*)C(C)*

C(NC*)C*

R₂

R₂ can be H, halo, cyano, OH, (C₁-C₆)alkyl, (C₂-C₈)alkenyl,(C₁-C₆)alkoxy, (C₃-C₁₀)heterocyclo, (C₃-C₁₀)cycloalkyl, aryl, orheteroaryl, any of which may be optionally substituted with 1 or moreR^(w) groups as allowed by valence; wherein R^(w) at each occurrence isindependently H, halo, cyano, nitro, oxo, amino, alkyl, haloalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl,heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may befurther independently substituted with one or more groups selected fromthe group consisting of halo, cyano, oxo(C₃-C₁₀)heterocyclo,(C₃-C₁₀)cycloalkyl, —(CH₂)_(n)—(C₃-C₁₀) cycloalkyl,—(CH₂)_(n)—(C₃-C₁₀)heterocyclo, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl,aryl, and heteroaryl, wherein n is 0, 1, 2, 3, 4, 5, or 6.

In some embodiments, R₂ is selected from the groups listed in Table 2.

TABLE 2 R₂ substitutent A—Cl C*

C(CC(Cl)*)C*

FC(F)(F)*

C(CC(F)*)C* A—F F*

C(CC(N(C)C)*)C*

N#C*

C(CC(N)*)C*

C(═C*)C*

C(CC*)C*

CO*

C(CC*)C* A— C*

C(C(C*)C)C*

ClN(C(═O)*)CCCCCl

C(N*)CC* A [*H]

C(NC*)C(C)*

C(C(Cl)C*)C*

C(NC*)C*

c1ccc(C(c2ccccc2)NC(═O)[C@H]2N3C(═O)[C@@H](NC(═O)[C@@H](NC)C)CN(S(═O)(═O)*)CC[C@H]3CC2)cc1

R₃

R₃ can be H, halo, cyano, OH, (C₁-C₆)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)carboxyalkyl; N—(C₁-C₆)alkylaminocarbonyl, (C₁-C₆)alkoxy,(C₁-C₆)sulfonyl, (C₃-C₁₀)heterocyclo, (C₃-C₁₀)cycloalkyl, aryl, orheteroaryl, any of which may be optionally substituted with 1 or more Rwgroups as allowed by valence; wherein Rw at each occurrence isindependently HK halo, cyano, nitro, oxo, amino, alkyl, haloalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl,heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may befurther independently substituted with one or more groups selected fromthe group consisting of halo, cyano, oxo(C3-C10)heterocyclo,(C3-C10)cycloalkyl, —(CH2)n-(C3-C10) cycloalkyl,—(CH2)n-(C3-C10)heterocyclo, —(CH2)n-aryl, —(CH2)n-heteroaryl, aryl, andheteroaryl, wherein n is 0, 1, 2, 3, 4, 5, or 6.

In some embodiments, R₃ is selected from the groups listed in Table 3.

TABLE 3 R₃ substituent A—Br Br*

NC(═O)*

c1c(C)cc(C)c(*)c1C A—Cl Cl* A—NH₂ N*

c1cc(C(F)(F)F)cc(*)c1

FC(F)(F)O*

OC(═O)CN(CC(═O)NCC*)S(═O)(═O)c1ccc(c2ccccc2)cc1

c1cc(F)cc(*)c1

FC(F)(F)* A—OH O*

c1cc(O*)ccc1F A—F F*

O[C@@](C)(C(F)(F)F)*

c1cc(S(═O)(═O)N2CCN(C(═O)*)CC2)ccc1C

N#C*

O[C@](C)(C(F)(F)F)*

c1cc(S(═O)(═O)N2CCN(CC(═O)N*)CCC2)ccc1F

O═[N+]([O−])*

OC(CC*)C*

c1cc(*)ccc1C#N

C(═C*)C* A [*H]

c1cc(*)ccc1C(C)(C)C

CC(═O)*

C(C(Br)C*)C*

c1cc(*)ccc1C(F)(F)F

CC(C)(C)*

C(C(Cl)C(Cl)C*)*

c1cc(*)ccc1C(C)C

CC(C)*

C(C(Cl)C*)C*

c1cc(*)ccc1CCN1CCC[C@H]1C

CC(O*)C

C(C(Cl)C*)C*

c1cc(*)ccc1CC

CCCCC*

C(C(Cl)C*)C*

c1cc(*)ccc1C

CCCCO*

C(C(OC)C(OC)C*)*

c1cc(*)ccc1Cl

CCCO*

C(C(OC)C*)C*

c1cc(*)ccc1F

CCO*

C(C(OC)C*)C*

c1cc(*)ccc1OC(F)(F)F

CN(C)S(═O)(═O)*

C(CC(Cl)*)C*

c1cc(*)ccc1OC(C)C

CO*

C(CC(F)*)C*

c1cc(*)ccc1OCCC

CS(═O)(═O)*

C(CC(N)*)C*

c1cc(*)ccc1OCC A— C*

C(CC*)C*

c1cc(*)ccc1OC

C═CC(═O)N*

C(N*)CC*

c1cc(*)cc2c1OCO2

C1N(S(═O)(═O)*)CCCCC1

C(C(C*)C)C*

c1ccc(COC(═O)N*)cc1

C1N(S(═O)(═O)*)C[C@@H](C)CC1

C(C(C*)C)C*

c1ccc(O*)cc1

N(C(═O)C)*

C(C(C*)CC)C*

c1ccc(*)c(Cl)c1

N(C(═O)OC)*

C(C(C*)C)C*

c1ccc(*)cc1

N(C[C@@H]1OCCC1)S(═O)(═O)*

C(C(C*)N)C*

c1ccc(C*)c(C*)c1

R₄

R₄ can be H, halo, cyano, OH, (C₁-C₆)alkyl, (C₂-C₈)akenyl,(C₂-C₈)carboxyalkyl; N—(C₁-C₆)akylaminocarbonyl, (C₁-C₆)alkoxy,(C₁-C₆)sulfonyl, (C₃-C₁₀)heterocyclo, (C₃-C₁₀)cycloalkyl, aryl, orheteroaryl, any of which may be optionally substituted with 1 or moreR^(w) groups as allowed by valence; wherein R^(w) at each occurrence isindependently H, halo, cyano, nitro, oxo, amino, alkyl, haloalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl,heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may befurther independently substituted with one or more groups selected fromthe group consisting of halo, cyano, oxo(C₃-C₁₀)heterocyclo,(C₃-C₁₀)cycloalkyl, —(CH₂)_(n)—(C₃-C₁₀) cycloalkyl,—(CH₂)_(n)—(C₃-C₁₀)heterocyclo, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl,aryl, and heteroaryl, wherein n is 0, 1, 2, 3, 4, 5, or 6.

In some embodiments, R₄ is selected from the groups listed in Table 4.

TABLE 4 R₄ substituent A—Cl Cl*

C(C(OC)C*)C*

FC(F)(F)*

C(CC*)C* A—F F*

C(CC*)C(N(C)C)* A— C*

N(SN*)* A—OH O*

C(C(C*)C)C*

OC(CC*)C*

C(C(C*)CC)C* A [*H]

C(C(C*)C)C*

C(C(Br)C*)C*

C(C(C*)N(C)C)C*

C(C(Cl)C(Cl)C*)*

C(C(C*)N)C*

C(C(Cl)C*)C*

C(NC*)C*

C(C(Cl)C*)C*

c1ccc(C*)c(C*)c1

C(C(OC)C(OC)C*)*

N(ON*)*

C(C(OC)C*)C*

R₅

R₅ can be H, halo, cyano, OH, (C₁-C₆)alkyl, (C₂-C₈)akenyl,(C₂-C₈)carboxyalkyl; N—(C₁-C₆*akylaminocarbonyl, (C₁-C₆)alkoxy,(C₁-C₆)sulfonyl, (C₃-C₁₀)heterocyclo, (C₃-C₁₀)cycloalkyl, aryl, orheteroaryl, any of which may be optionally substituted with 1 or moreR^(w) groups as allowed by valence; wherein R^(w) at each occurrence isindependently H, halo, cyano, nitro, oxo, amino, alkyl, haloalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl,heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may befurther independently substituted with one or more groups selected fromthe group consisting of halo, cyano, oxo(C₃-C₁₀)heterocyclo,(C₃-C₁₀)cycloalkyl, —(CH₂)_(n)—(C₃-C₁₀) cycloalkyl,—(CH₂)_(n)—(C₃-C₁₀)heterocyclo, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl,aryl, and heteroaryl, wherein n is 0, 1, 2, 3, 4, 5, or 6.

In some embodiments R₅ is selected from the groups listed in Table 5.

TABLE 5 R₅ substituent A—Br Br*

ONC(═O)* A—Cl Cl* A [*H]

FC(F)(F)*

C(CC*)C(N(C)C)* A—F F*

C(CC*)C* A—I I*

C(C(C*)N(C)C)C*

N#C*

C(NC*)C*

CO*

c1nc(N)cnc1c1ccc(*)cc1F A— C*

N(ON*)*

N(SN*)*

R₆

R₆ can be H, halo, cyano, OH, (C₁-C₆)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)carboxyalkyl; N—(C₁-C₆)akylaminocarbonyl, (C₁-C₆)alkoxy,(C₁-C₆)sulfonyl, (C₃-C₁₀)heterocyclo, (C₃-C₁₀)cycloalkyl, aryl, orheteroaryl, any of which may be optionally substituted with 1 or moreR^(w) groups as allowed by valence; wherein R^(w) at each occurrence isindependently H, halo, cyano, nitro, oxo, amino, alkyl, haloalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl,heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may befurther independently substituted with one or more groups selected fromthe group consisting of halo, cyano, oxo(C₃-C₁₀)heterocyclo,(C₃-C₁₀)cycloalkyl, —(CH₂)_(n)—(C₃-C₁₀) cycloalkyl,—(CH₂)_(n)—(C₃-C₁₀)heterocyclo, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl,aryl, and heteroaryl, wherein n is 0, 1, 2, 3, 4, 5, or 6.

In some embodiments, R₆ is selected from the groups listed in Table 6.

C(═O)[C@@H](NC(═O)[C@@H](N*)C(C)C)CC(C)C

OC(═O)CN(C(═O)[C@@H](NC(═O) [C@H]1N(C(═O)OCc2ccccc2)CCC1)CC(C)C)*

C(═O)[C@H](NC(═O)[C@@H](N*)C(C)C)CC(C)C

OC(═O)CN(C(═O)[C@H]1N(*)CCC1)C1CCN(CCc2ccccc2)CC1

C(C(═O)CC)N([C@@H]1C(═O)N([C@H](C(═O)N2CCOCC2)C)CC1)*

OC(═O)CN(C(═O)[C@H](N*)CCCN═C(N)N)CCCC

C(C(═O)N1CCCC1)N(CC)*

OC(═O)CN([C@@H]1C(═O)N([C@H](C(═O)N2CCOCC2)C)CC1)*

C(C(═O)N1CCCC1)N(C1CCCCC1)*

OC(═O)CNC(═O)[C@H](NC[C@@H]1N(*)CCC1)CC(C)C

C(C(═O)N1CCCC1)N1CCN(*)CC1

OC(═O)C[C@@H](C(═O)NCCCc1ccccc1)N*

C(C(═O)N1CCN(C(═O)OCC)CC1)N(C1CCCCC1)*

OC(═O)C[C@@H](C(═O)NCCc1ccc(F)cc1)N*

C(C(═O)N1CCN(*)CC1)CN1C(═O)[C@H]2CCCC[C@@H]2C1═O

OC(═O)C[C@@H](C(═O)NCCc1ccc(S(═O)(═O)N)cc1)N*

C(C(═O)N1CCOCC1)N(CC)*

OC(═O)C[C@@H](C(═O)NCCc1ccccc1)N*

CC(═O)N1C(═O)[C@@H](C)[C@H]2N(C(═O)[C@H]3N(*)CCC3)CC[C@H]12

OC(═O)C[C@@H](C(═O)N[C@@H](C(═O)N)[C@H](O)C)NC(═O)[C@@H](N*)CC(C)C

CC(═O)N1C(═O)[C@H](C)[C@@H]2N(C(═O)[C@H]3N(*)CCC3)CC[C@@H]12

OC(═O)[C@@H](N(CC(C)C)*)CNC(═O)OCC1c2ccccc2c2ccccc12

CC(═O)N1CCN(*)CC1

OC(═O)[C@@H](NC(═O)[C@@H](NC(═O)CN*)C)C

CC(OC(═O)N1C[C@H]2N(*)C[C@@H]1C2)(C)C

OC(═O)[C@@H](NC(═O)[C@@]1(C)N(*)CCC1)Cc1ccccc1

CC(C(═O)N1CCN(*)CC1)C

OC(═O)[C@@H](NC(═O)[C@H]1N(*)CCC1)CNC(═O)CCc1ccccc1

CC(C)CC(═O)N1CCN(*)CC1

OC(═O)[C@@H](NC(═O)[C@H]1N(*)CCC1)CNC(═O)NCc1ccccc1

CCC[C@H]1C(═O)N(*)[C@H]2CCN(C(═O)CCN3CCCCC3)[C@H]12

OC(═O)[C@@H](NC(═O)[C@H]1N(*)CCC1)CNC(═O)Nc1ccccc1

CCN1CCN(C(═O)[C@@H]2CN(*)CCC2)CC1

OC(═O)[C@@H](NC(═O)[C@H]1N(*)CCC1)Cc1ccccc1

CCOC(═O)N1CCC(N2CCN(*)CC2)CC1

OC(═O)[C@@H](NC(═O)[C@]1(C)N(*)CCC1)Cc1ccccc1

CCOC(═O)N1CCN(C(═O)[C@@H]2CN(*)CCC2)CC1

OC(═O)[C@@H](N*)CNC(═O)CN1C(═O)[C@H](CCC2CCNCC2)CCC1

CCOC(═O)[C@@H]1CN(*)CCC1

OC(═O)[C@@H](N[C@H](C(═O)NC1CCN(C(═O)OCC)CC1)CCc1ccccc1)CCN*

CC1(C)C(C(═O)N2C(═O)[C@@H](C)[C@H]3N(C(═O)[C@H]4N(*)CCC4)CC[C@H]23)C1(C)C

OC(═O)[C@@H](N[C@H](C(═O)N[C@H](C(═O)NC)Cc1ccccc1)CCc1ccccc1)CCN*

CC1(C)N(C(═O)C2CCCCC2)CCN(*)C1

OC(═O)[C@@H](N[C@H](C(═O)N1CCN(S(═O)(═O)C)CC1)CCc1ccccc1)CCN*

CC1CCN(CC[C@H]2N(*)CCCC2)CC1

OC(═O)[C@@H](N1C(═O)[C@H]2N(*)CC[C@H]2C1)Cc1ccccc1

CC1CCN(CC[C@H]2N(*)CCC2)CC1

OC(═O)[C@@H]1CCCC[C@H]1NC(═O)CN(C1CCCCC1)*

CC1CCN(CC[C@@H]2N(*)CCCC2)CC1

OC(═O)[C@H]1CN(*)CCC1

CC1CCN(CC[C@@H]2N(*)CCC2)CC1

OC(═O)[C@H]1CN(c2ccccc2)C(═O)[C@H]1N*

CN(CC(═O)N1CCCCC1)*

OC(═O)[C@@]12C[C@H]3C[C@@H](C1)[C@H](NC(═O)C1(N(C)*)CC1[C@H](C3)C2

CN(CC(═O)N1CCCC1)*

OC(═O)[C@H](N(CCNC(═O)c1cccc(C(═O)NCCN([C@@H](C(═O)N(C)C)C(C)C)*)c1)S(═O)(═O)c1ccc(c2ccccc2)cc1)C(C)C

CN(CC(═O)N1CCOCC1)*

OC(═O)[C@H](NC(═O)C1CCN(C(═O)[C@@H](N*)C(C)C)CC1)CCCCC

CN(CC(═O)N1CC[C@H]2N(C(═O)C3CC3)C(═O)[C@H](C)[C@H]12)*

OC(═O)[C@H](NC(═O)[C@@H](NC(═O)CN*)C)C

CN(CC(═O)N1C[C@H](C)O[C@@H](C)C1)*

OC(═O)[C@H](NC(═O)[C@@]1(C)N(*)CCC1)Cc1ccccc1

CN([C@@H](C)CCN1CCC[C@@H](C)C1)*

OC(═O)[C@H](NC(═O)[C@H](NC(═O)CN*)C)C

CN([C@@H](C)CCN1CCC[C@H](C)C1)*

OC(═O)[C@H](NC(═O)[C@]1(C)N(*)CCC1)Cc1ccccc1

CN([C@H](C)CCN1CCC(C)CC1)*

OC(═O)[C@H](N*)CNC(═O)Cc1ccccc1

CN([C@H](C)CCN1CCC[C@@H](C)C1)*

OC(═O)[C@H](N*)CNC(═O)OC(C)(C)C

CN([C@H](C)CCN1CCC[C@H](C)C1)*

OC(═O)[C@H](N*)CNC(═O)c1ccccc1

CN([C@@H]1C(═O)N(CC(═O)N2CCCCCC2)CC1)*

OC(═O)[C@H](N*)CNC(═O)c1ccncc1

CN([C@@H]1C(═O)N(CC(═O)N2CCCCC2)CC1)*

OC(═O)[C@@H]1CN(C(═O)CC2CCN(C(═O)OC(C)(C)C)CC2)C[C@H]1C(═O)NC[C@@H](C(═O)OC(C)(C)C)N*

CN([C@@H]1C(═O)N([C@H](C(═O)N2CCCCC2)CC1)*

OC(═O)[C@@H]1CN(C(═O)[C@@H](/C═C/CN═C(N)N)N*)CCC1

CN([C@@H]1C(═O)N([C@H](C(═O)N2CCOCC2)C)CC1)*

OC(═O)[C@@H]1CN(*)CCC1

CN1C(═O)CC[C@@]2(N(C)CCN(*)C2)CC1

OC(═O)[C@@H]1N(C(═O)CN(CC(═O)[C@@H](NC(═O)c2ccccc2)Cc2ccccc2)*)C═CC1

CN1CCN(C(═O)[C@@H]2CN(*)CCC2)CC1

OC(═O)[C@@H]1N(C(═O)[C@@H](/C═C/CN═C(N)N)N*)CCCC1

CN1CCN(C(═O)[C@@H]2N(*)CCCC2)CC1

OC(═O)[C@@H]1N(C(═O)[C@H](N*)(CCCN═C(N)N)CCCCC1

CN1CCN(CCCC[C@H]2CN(*)C[C@@H]3CCCN4CCC[C@H]2[C@H]34)CC1

OC(═O)[C@@H]1N(C(═O)[C@H](N*)CCCN═C(N)N)CC[C@H](C(C)C)C1

CN1CCN(*)CCC1

OC(═O)[C@@H]1N(C(═O)[C@H](N*)CCCN═C(N)N)CC[C@H](CC)C1

C═CC(═O)N[C@H]1CN(*)CC1

OC(═O)[C@@H]1N(C(═O)[C@H](N*)CCCN═C(N)N)CC[C@H](C)C1

C═CC(═O)N[C@@H]1CN(*)CC1

OC(═O)[C@@H]1N(*)CCCC1

C═CC[C@H]1C(═O)N(*)[C@H]2CCN(C(═O)OCc3ccccc3)[C@H]12

OCCN1CCN(S(═O)(═O)c2ccc(C)cc2)CCN(CCO)CCN(*)CC1

C1CCC(C(═O)N2[C@@H](C)CN(*)C[C@H]2C)CC1

OCCN1CCN(*)CC1

C1CCC(C(═O)N2[C@@H]3CN(*)C[C@H]2CC3)CC1

OCCN1CCN(S(═O)(═O)c2ccc(C)cc2)CCCN(Cc2ccccc2)CCCN(*)C1

C1CCC(C(═O)N2[C@@H]3CN(*)C[C@H]2C3)CC1

OCN[C@H](C[C@@H]1C═C[C@H](OCCCC(═O)NCC(C)C)CC1)[C@H](O)CN(CCC(C)C)*

C1CCC(N2C[C@H]3N(*)C[C@@H]2C3)C1

OC[C@@H](C(═O)N[C@H](/C═C/S(═O)(═O)CC(C)C)NC(═O)[C@@H](*N)CC(═O)NCC(C)(C)C

C1N(C(═O)C2CCCCC2)CCN(*)C1

OC[C@@H](C(═O)N1CC[C@@H](C)C[C@@H]1C(═O)NCCCCN═C(N)N)N*

C1N(C(═O)C2CCCCC2)C[C@@H](C)N(*)C1

OC[C@@H](C(═O)N1CC[C@H](C)C[C@H]1C(═O)NCCCCN═C(N)N)N*

C1N(C(═O)C2CCCCC2)[C@H](C(F)(F)F)CN(*)C1

OC[C@H]1N(CCCCCC(═O)NCCN*)C[C@H](O)[C@@H](O)[C@@H]1O

C1N(C(═O)C2CCCCC2)[C@H](C)CN(*)C1

OC[C@H]1N[C@H](CN*)[C@@H](O)[C@H]1O

C1N(C(═O)C23CC4CC(CC(C4)C2)C3)CCN(*)C1

OC[C@H]1N[C@H](CN*)[C@@H](O)[C@@H]1O

C1N(C(═O)N2CC[C@@]3(C2)CN(*)CCC3)CCCN(C2CCC2)C1

OC[C@@H]1N(CC2CC2)[C@H](CN*)[C@H]1c1ccccc1

C1N(C(═O)[C@@H]2CN(*)CCC2)CCC1

OC1(CN2CCN(Cc3ccccc3)CC2)CCN(*)CC1

C1N(C2CCCCC2)CCN(*)C1

OC1C2(C)(CN(S(═O)(═O)c3ccc(C)cc3)CC1(C)CN(*)C2

C1N(S(═O)(═O)C)[C@]2(CN(*)CCC2)CC1

ONC(═O)[C@H]1N(*)C[C@@H](NC(═O)CNC(═O)[C@@H](N)C(C)C)C1

C1N(*)CCC(N2C[C@H](C)O[C@@H](C)C2)C1

ONC(═O)[C@H]1N(*)C[C@@H](NC(═O)CNC(═O)[C@@H](N)CC(C)C)C1

C1N(*)CCC1

ONC(═O)[C@H]1N(*)C[C@@H](NC(═O)CNC(═O)[C@H](N)[C@@H](C)CC)C1

C1N(*)[C@@H](C(═O)N2CC[C@H]3N(C(═O)C4CC4)C(═O)[C@H](C)[C@H]23)CCC1

ONC(═O)[C@H](N(/C═C/C(C)C)*)C(C)C

C1N(*)[C@H]2CN(C(═O)C3CC3)C[C@H]2CC1

ONC(═O)[C@@H]1N(*)CCN(S(═O)(═O)c2ccc(OC)cc2)CC1

C1N(*)[C@H](C(═O)N2CC[C@@H]3N(C(═O)C4CC4)C(═O)[C@@H](C)[C@@H]23)CC1

ONC(═O)[C@@H]1N(*)C[C@@H](N(C(═O)[C@@H](O)CCc2ccccc2)CCC)C1

C1N(*)[C@H](C(═O)N2CC[C@@H]3N(C(═O)[C@H]4[C@@H](C)[C@H]4C)C(═O)[C@@H](C)[C@@H]23)CC1

ONC(═O)[C@@H]1N(*)C[C@@H](N2CCCCC2)C1

C1N(*)[C@H](C(═O)N2CC[C@@H]3N(C(═O)[C@@H]4C[C@@H]4C)C(═O)[C@@H](C)[C@@H]23)CC1

ONC(═O)[C@@H]1N(*)C[C@@H](N2CCCC2)C1

C1N([C@@H](C(═O)N2CCCC2)C)CCN(*)C1

ONC(═O)[C@@H]1N(*)C[C@@H](N2CCOCC2)C1

C1N([C@@H](C(═O)N2C[C@@H](C)C[C@@H](C)C2)C)CCN(*)C1

ONC(═O)[C@@H]1N(*)C[C@@H](O)[C@@H](O)[C@@H]1O

C1OCCN(C(═O)[C@H]2N(*)[C@H]3CCCCC(═O)[C@H]3C2)C1

OS(O)(O[C@@H]1CN(*)[C@@H](C(═O)N[C@H](C═O)Cc2ccccc2)C1)C

C1OCCN(C(═O)[C@@H]2CN(*)CCC2)C1

O[C@@](C(═O)N1CCN(*)[C@H](C)C1)(C)C(F)(F)F

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N—C(N)N1CCC[C@H](C(—O)NC[C@H]2N(C(—O)[C@@H](N*)[C@@H](O)C)CCC2)C1

c1ccc(N2C(═O)CO[C@H]3CN(*)C[C@@H]23)cc1

N═C(N)N1CCC[C@H](C(═O)NC[C@H]2N(C(═O)[C@H](N*)[C@@H](O)C)CCC2)C1

c1ccc(N2C(═O)C[C@@H](N*)C2)cc1

N═C(N)N1CCC[C@H](CNC(═O)CN*)C1

c1ccc(N2CCN(C(═O)[C@@H]3CN(*)CCC3)CC2)cc1

N—C(N)N1CCC[C@H](CNC(—O)C[C@@H](C(—O)N2CCC(C(—O)OCC)CC2)N*)C1

c1ccc(N2CCN(CCCN(CC3CCCCC3)*)CC2)cc1

N═C(N)N1CCC[C@H](CNC(═O)C[C@@H](C(═O)N2CCC(C(═O)O)CC2)N*)C1

c1ccc(N2CCN(CCCN(CC3CC3)*)CC2)cc1

N═C(N)N1CCC[C@H](CNC(═O)C[C@@H](C(═O)N2CCCCCCC2)N*)C1

c1ccc(N2CCN(CCCN*)CC2)cc1

N—C(N)N1CCC[C@H](CNC(—O)C[C@@H](C(—O)N2CCOCC2)N*)C1

c1ccc(N2CCN(CC[C@@H](N*)C)CC2)cc1

N═C(N)N1CCC[C@H](NC(═O)[C@@H](NC(═O)[C@H](N*)CO)C)[C@@H]1O

c1ccc(N2CCN(C3CCN(*)CC3)CC2)cc1

N═C(N)N1CCC[C@H](NC(═O)[C@H]2N3C(═O)[C@H](N*)CCC[C@H]3CC2)[C@@H]1O

c1ccc(OCCC(═O)N2CCN(*)CC2)cc1

N—C(N)N1CCN(*)CCC1

c1ccc(OCCCN2C[C@@H]3O[C@@H](CN(CCN*)C3)C2)c(F)c1

N═C(N)[C@H]1CCC[C@H](NC(═O)CN2C(═O)[C@@H](N*)CCCC2)[C@@H]1O

c1ccc(OCCNC(═O)CCN*)cc1

N═C(N)[C@H]1CCC[C@H](NC(═O)CN2C(═O)[C@@H](N*)CCC2)[C@@H]1O

c1ccc(S(═O)(═O)N(Cc2ccc(Br)cc2)[C@H]2CNC[C@@H]2N(Cc2ccc(Br)cc2)*)cc1

N—C(c1ccc(C(—O)[C@H]2N(C(—O)[C@@H](N*)CO)CCC2)cc1)N

c1ccc(S(═O)(═O)N(Cc2ccc(C(F)(F)F)cc2)[C@H]2CNC[C@@H]2N(Cc2ccc(C(F)(F)F)cc2)*)cc1

N═C(c1ccc(CNC(═O)CNC(═O)[C@H](N*)CO)cc1)N

c1ccc(S(═O)(═O)N(Cc2ccc(I)cc2)[C@H]2CNC[C@@H]2N(Cc2ccc(I)cc2)*)cc1

N═C(c1cccc(CN2C(═O)C[C@H](N*)C2)c1)N

c1ccc(S(═O)(═O)N2CCC(N(C(═O)[C@H]3N(*)CCC3)C)CC2)cc1

N—C(c1cccc(CN2C(—O)[C@@H](N(CC(—O)N)*)CC2)c1)N

c1ccc(S(═O)(═O)N2CCC3(OCCN3*)CC2)cc1

N═C(c1cccc(CN2C(═O)[C@@H](N(CC(═O)O)*)CC2)c1)N

c1ccc(S(═O)(═O)N2CCN(C(═O)CCN*)CC2)cc1

N═C(c1cccc(CN2C(═O)[C@@H](N(CCC(═O)N)*)CC2)c1)N

c1ccc(S(═O)(═O)N2CCN(*)[C@@H](C(═O)NC3CCCCC3)C2)cc1

N—C(c1cccc(CN2C(—O)[C@@H](N(CC)*)CC2)c1)N

c1ccc(S(═O)(═O)N2CCN(*)[C@@H](C(═O)NC3CCCCCC3)C2)cc1

N═C(c1cccc(CN2C(═O)[C@@H](N(C)*)CC2)c1)N

c1ccc(S(═O)(═O)N2CCN(*)[C@H](C(═O)Nc3ccc(Br)cc3)C2)cc1

N═C(c1cccc(CN2C(═O)[C@@H](N*)CC2)c1)N

c1nc(N2CC[C@H]3N(*)CC[C@H]23)ncc1

N—C(c1cccc(CN2C(—O)[C@H](N(C)*)CC2)c1)N

c1nccc(N2CCN(C(═O)C3CN(*)C3)CC2)c1

N═C(c1cccc(CN2C(═O)[C@H](N*)CC2)c1)N

c1ncn(CCC(═O)N2CCN(*)CC2)n1

N═C(c1cccc(CN2CC[C@H](N*)C2)c1)N

c1sc(CN2CCCC[C@H]3CN(*)C[C@@H]23)cc1

Additional or Alternative Examples

In examples, after the virtual screening (and/or at any suitable timeand frequency), the first nine molecules with binding energy less than−9.5 kcal/mol against the HtrA enzymes (however, any suitable criteriacan be used, such as any suitable binding energy threshold; etc.) werechosen as the selected candidates (e.g., called “Dataset 1”, FIG. 7).Additionally or alternatively, three additional or alternative moleculeswith molecular weight higher than 500 Da (however, any suitable criteriacan be used, such as any suitable molecular weight threshold; etc.) werealso considered in the dataset due to their high energy of binding(e.g., CHEMBL83186, CHEMBL421919, CHEMBL3429004; etc.), but any suitablecriteria can additionally or alternatively be used.

TABLE 7 IUPAC nomenclature and canonical SMILES of specific examples ofselected candidates (Dataset 1). Compound # Molecule Canonical SMILESName 1 CHEMBL1515370 Cc1ccc(cc1)S(═O)(═O)N1CCCCN′-benzyl-N-[2-[(2R)-1-(4- (binding energy = −9.6[C@@H]1CCNC(═O)C(═O)NCc1ccccc1 methylphenyl)sulfonylpiperidin-2-kcal/mol) yl]ethyl]oxamide 2 CHEMBL1868353 NC(═O)C1CCN(CC1)C(═O)CN1-[2-[methyl(naphthalen-2- (binding energy = −9.6(S(═O)(═O)c1ccc2c(c1)cccc2)C ylsulfonyl)amino]acetyl]piperidine-4-kcal/mol) carboxamide 3 CHEMBL1880232 Cc1ccc(cc1)S(═O)(═O)N1CCC28-(4-methylphenyl)sulfonyl-4-(2,4,6- (binding energy = −9.6(CC1)OCCN2S(═O)(═O) trimethylphenyl)sulfonyl-1-oxa-4,8- kcal/mol)c1c(C)cc(cc1C)C diazaspiro[4.5]decane 4 CHEMBL2159481Fc1cc(ccc1F)S(═O)(═O)N[C@H] N-{1-[2-(2-Biphenylyloxy)ethyl]-3- (bindingenergy = −9.6 1CCN(C1)CCOc1ccccc1c1ccccc1 pyrrolidinyl}-3,4- kcal/mol)difluorobenzenesulfonamide 5 CHEMBL2172063 OC(═O)[C@H]1CCCN(C1)S(═O)1-(2-Anthrylsulfonyl)-3- (binding energy = −9.7(═O)c1ccc2c(c1)cc1c(c2)cccc1 piperidinecarboxylic acid kcal/mol) 6CHEMBL342904 O═C([C@H]1CCCN(C1)C(═[NH2])N)(3S)-1-Carbamimidoyl-N-({(2S)-1- (binding energy = −9.7NC[C@@H]1CCCN1C(═O) [N-(2-naphthylsulfonyl)glycyl]-2- kcal/mol)CNS(═O)(═O)c1ccc2c(c1)cccc2 pyrrolidinyl}methyl)-3-piperidinecarboxamide 7 CHEMBL421919 O═C([C@H]1CCCN(C1)C(3S)-1-Carbamimidoyl-N-({(2S)-1- (binding energy = −10.2(=[NH2])N)NC[C@@H]1CCCN1C [N-(2-naphthylsulfonyl)-L-alanyl]-2- kcal/mol)(═O)[C@@H](NS pyrrolidinyl}methyl)-3 - (═O)(═O)c1ccc2c(c1)cccc2)Cpiperidinecarboxamide 8 CHEMBL489852 O═C(N1CCN(C[C@H]1C(F)(F)F)Cyclohexyl[4-(1-naplithylsulfonyl)- (binding energy = −9.7S(═O)(═O)c1cccc2c1cccc2)C1CCCCC1 2-(trifluoromethyl)-1- kcal/mol)piperazinyl]methanone

Additional or Alternative Examples

In examples, after the virtual screening (and/or at any suitable timeand frequency), the first nine molecules with binding energy less than−9.5 kcal/mol against the HtrA enzymes (however, any suitable criteriacan be used, such as any suitable binding energy threshold; etc.) werechosen as the selected candidates (e.g., called “Dataset 1”, FIG. 7).Additionally or alternatively, three additional or alternative moleculeswith molecular weight higher than 500 Da (however, any suitable criteriacan be used, such as any suitable molecular weight threshold; etc.) werealso considered in the dataset due to their high energy of binding(e.g., CHEMBL83186, CHEMBL421919, CHEMBL342904; etc.), but any suitablecriteria can additionally or alternatively be used.

TABLE 7 IUPAC nomenclature and canonical SMILES of specific examples ofselected candidates (Dataset 1). Compound # Molecule Canonical SMILESName 1 CHEMBL1515370 Cc1ccc(cc1)S(═O)(═O)N1CCCCN′-benzyl-N-[2-[(2R)-1-(4- (binding energy = −9.6[C@@H]1CCNC(═O)C(═O)NCc1ccccc1 methylphenyl)sulfonylpiperidin-2 -kcal/mol) yl]ethyl]oxamide 2 CHEMBL1868353 NC(═O)C1CCN(CC1)C(═O)CN1-[2-[methyl(naphthalen-2- (binding energy = −9.6(S(═O)(═O)c1ccc2c(c1)cccc2)C ylsulfonyl)amino]acetyl]piperidine-4-kcal/mol) carboxamide 3 CHEMBL1880232 Cc1ccc(cc1)S(═O)(═O)N1CCC28-(4-methylphenyl)sulfonyl-4-(2,4,6- (binding energy = −9.6(CC1)OCCN2S(═O)(═O) trimethylphenyl)sulfonyl-1-oxa-4,8- kcal/mol)c1c(C)cc(cc1C)C diazaspiro[4.5]decane 4 CHEMBL2159481Fc1cc(ccc1F)S(═O)(═O)N[C@H] N-{1-[2-(2-Biphenylyloxy)ethyl]-3- (bindingenergy = −9.6 1CCN(C1)CCOc1ccccc1c1ccccc1 pyrrolidinyl}-3,4- kcal/mol)difluorobenzenesulfonamide 5 CHEMBL2172063 OC(═O)[C@H]1CCCN(C1)S(═O)1-(2-Anthrylsulfonyl)-3- (binding energy = −9.7(═O)c1ccc2c(c1)cc1c(c2)cccc1 piperidinecarboxylic acid kcal/mol) 6CHEMBL342904 O═C([C@H]1CCCN(C1)C(═[NH2])N)(3S)-1-Carbamimidoyl-N-({(2S)-1- (binding energy = −9.7NC[C@@H]1CCCN1C(═O) [N-(2-naphthylsulfonyl)glycyl]-2- kcal/mol)CNS(═O)(═O)c1ccc2c(c1)cccc2 pyrrolidinyl}methyl)-3-piperidinecarboxamide 7 CHEMBL421919 O═C([C@H]1CCCN(C1)C(=[N(3S)-1-Carbamimidoyl-N-({(2S)-1- (binding energy = −10.2H2])N)NC[C@@H]1CCCN1C [N-(2-naphthylsulfonyl)-L-alanyl]-2- kcal/mol)(═O)[C@@H](NS pyrrolidinyl}methyl)-3 - (═O)(═O)c1ccc2c(c1)cccc2)Cpiperidinecarboxamide 8 CHEMBL489852 O═C(N1CCN(C[C@H]1C(F)(F)F)Cyclohexyl[4-(1-naplithylsulfonyl)- (binding energy = −9.7S(═O)(═O)c1cccc2c1cccc2)C1CCCCC1 2-(trifluoromethyl)-1- kcal/mol)piperazinyl]methanone

TABLE 8 Specific examples of ADME properties of the selected candidates(Dataset 1) obtained in SwissADME. In specific examples, Compounds 2, 6and 7 appeared as a good drug candidates, as they are predicted do notinhibit cytochromes P450 isoforms. Compound 1 2 3 4 5 6 7 8 9 MW 443.56389.47 478.62 458.52 369.43 501.62 515.65 454.51 592.75 #H-bond 5 5 7 75 5 5 7 8 acceptors #H-bond 2 1 0 1 1 4 4 0 4 donors TPSA 103.96 109.16100.75 67.02 83.06 159.24 159.24 66.07 176.51 Consensus 2.62 1.35 3.234.11 2.94 −0.27 0.23 4.01 1.64 Log P Ali Moderately Soluble ModeratelyModerately Moderately Soluble Moderately Moderately Moderately Classsoluble soluble soluble soluble soluble soluble soluble GI High HighHigh High High Low Low High Low absorption BBB No No No No No No No NoNo permeant CYP1A2 No No No No Yes No No No No inhibitor CYP2C19 Yes NoYes Yes No No No Yes No inhibitor CYP2C9 Yes No Yes Yes Yes No No Yes Noinhibitor CYP2D6 Yes No No Yes No No No Yes No inhibitor CYP3A4 Yes NoYes Yes Yes No No Yes Yes inhibitor

In examples, in a second filter (and/or any suitable filter able to beapplied at any suitable time and frequency; etc.), molecules having abinding energy higher than −9.4 kcal/mol and less than −8.9 kcal/mol(e.g., which can be an improvement over the reported compound) (however,any suitable criteria can be used, such as any suitable binding energythreshold; etc.) were chosen as the Dataset 2. In specific examples, twomolecules having MW>500 were also included in the dataset 2, as theshowed high binding affinity.

TABLE 9 IUPAC nomenclature and canonical SMILES of specific examples ofthe selected candidates (Dataset 2). Compound # Molecule CanonicalSMILES Name 10 CHEMBL168720 NC(═N)NCCC[C@H](C(═O)N1N-[5-Carbamimidamido-1-(4 - CCOCC1)NS(═O)(═O)c1ccc2c(c1)cccc2morpholinyl)-1-oxo-2-pentanyl]- 2-naphthalenesulfonamide 11 CHEMBL168727NC(═N)NCCC[C@H](C(═O) N-[1-(1-Azepanyl)-5-N1CCCCCC1)NS(═O)(═O)c1ccc2c(c1)cccc2 (carbamimidamido-1-oxo-2-pentanyl]-2- naphthalene sulfonamide 12 CHEMBL1891859Cc1ccc(c(c1)S(═O)(═O)N1CCC N-Cyclopentyl-N′-({1-[(2,5-[C@@H]1CNC(═O)C(═O)NC1CCCC1)C dimethylphenyl)sulfonyl]-2-pyrrolidinyl}methyl)ethanediamide 13 CHEMBL1923450O═C1N(CCC[C@@H]1NS(═O) N-{(3S)-2-Oxo-1-[2-oxo-2-(1-(═O)c1ccc2c(c1)cccc2)CC(═O)N1CCCC1 pyrrolidinyl)ethyl]-3-piperidinyl}-2- naphthalene sulfonamide 14 CHEMBL1923452Clc1ccc2c(c1)cc(cc2)S(═O)(═O) 7-Chloro-N-{(3S)-2-oxo-1-[2-N[C@H]1CCCN(C1═O)CC(═O)N1CCCC1 oxo-2-(1-pyrrolidinyl)ethyl]-3-piperidinyl}-2- naphthalenesulfonamide 15 CHEMBL212360Clc1ccc2c(c1)ccc(c2)S(═O)(═O) 6-Chloro-N-methyl-N-{(3S)-2-N([C@H]1CCN(C1═O)CC(═O)N1CCCCC1)C oxo-1-[2-oxo-2-(1-piperidinyl)ethyl]-3- pyrrolidinyl}-2- naphthalenesulfonamide 16CHEMBL2152233 O═C([C@@]1(C)CCCN1S(═O) 1-(4-Biphenylylsulfonyl)-N-(═O)c1ccc(cc1)c1ccccc1)N[C@@H]1 [(2s,5R)-5-hydroxyadamantan-2-[C@@H]2C[C@@H]3C[C@H]1C[C@](C2)(C3)O yl]-2-methyl-D-prolinamide 17CHEMBL227136 NC(═[NH2])NCCC[C@@H](C(═O) N-[(2S)-5-carbamimidamido-1-N1CCOCC1)NS(═O)(═O)c1cccc2c1cccc2 (morpholin-4-yl)-1-oxopentan-2-yl]naphthalene-1-sulfonamide 18 CHEMBL227246 NC(═N)NCCC[C@@H](C(═O)N-[(2S)-5-carbamimidamido-1- N1CCNCC1)NS(═O)(═O)c1cccc2c1cccc2oxo-1-(piperazin-1-yl)pentan-2- yl]naphthalene-1-sulfonamide 19CHEMBL227406 NC(═[NH2])NCCC[C@@H](C(═O) N-[(2S)-5-carbamimidamido-1-N1CCCCC1)NS═O)(═O)c1cccc2c1cccc2 oxo-1-(piperidin-1-yl)pentan-2-yl]naphthalene-1-sulfonamide 20 CHEMBL301610 O═C([C@@H]1CCCN1S(═O)(3S,3aR,6aS)-1-Acetyl-4-{[(2S)- (═O)c1cccc2c1cccc2N(C)C)N1CC1-{[5-(dimethylamino)-1- [C@H]2[C@H]1[C@H](C)C(═O) naphthyl]sulfonyl}-2-N2C(═O)C pyrrolidinyl]carbonyl}-3- methylhexahydropyrrolo[3,2-b]pyrrol-2(1H)-one 21 CHEMBL342043 O═C([C@@H]1CCCN1S(═O)(═O)(3S,3aR,6aS)-1- c1ccc2c(c1)cccc2)N1CC[C@H]2 (Cyclopropylcarbonyl)-3-[C@H]1[C@H](C)C(═O)N2C methyl-4-{[(2S)-1-(2- (═O)C1CC1naphthylsulfonyl)-2- pyrrolidinyl]carbonyl}hexahydropyrrolo[3,2-]pyrrol-2(1H)-one 22 CHEMBL352178 O═C(CN1CCCC[C@@H]C1═O)4-(2-Oxo-3-{(3S)-2-oxo-3- NS(═O)(═O)c1ccccc1)CC1CCN[(phenylsulfonyl)amino]-1- (CC1)C(═[NH2])N azepanyl}propyl)-1-piperidinecarboximidamide 23 CHEMBL354149 NC(═[NH2])NCCC[C@H](C(═O)N-[1-(1-Azepanyl)-5- N1CCCCCC1)NS(═O)(═O)c1cccc2c1cccc2carbamimidamido-1-oxo-2- pentanyl]-1- naphthalene sulfonamide 24CHEMBL3740086 N#C[C@@H](NC(═O)[C@@H] N-[(1S)-3-Amino-1-cyano-3-1CCCN1S(═O)(═O)c1ccc(cc1)c1ccc(cc1)C(F)(F)F) oxopropyl]-1-{[4′- CC(═O)N(trifluoromethyl)-4- biphenylyl]sulfonyl}-L- prolinamide 25CHEMBL3740253 N#C[C@@H](NC(═O)[C@@H] N-[(1S)-3-Amino-1-cyano-3-1CCCN1S(═O)(═O)c1ccc(cc1)c1ccc(cc1)C)CC oxopropyl]-1-[(4′-methyl-4-(═O)N biphenylyl)sulfonyl]-L- prolinamide 26 CHEMBL3740368N#C[C@@H](NC(═O)[C@@H] N-[(1S)-3-Amino-1-cyano-3-1CCCN1S(═O)(═O)c1ccc(cc1)c1ccc(cc1)C#N)CC oxopropyl]-1-[(4′-cyano-4-(═O)N biphenylyl)sulfonyl]-L- prolinamide 27 CHEMBL3741666N#C[C@@H](NC(═O)[C@@H] N-[(1S)-3-Amino-1-cyano-3-1CCCN1S(═O)(═O)c1ccc(cc1)c1cccc(c1)C(F)(F)F) oxopropyl]-1-{[3′- CC(═O)N(trifluoromethyl)-4- biphenylyl]sulfonyl}-L- prolinamide 28 CHEMBL374524O═C([C@@H](N1CC[C@@H] (2S)-2-[(3S)-3-{[(6-Chloro-2-(C1═O)NS(═O)(═O)c1ccc2c(c1)ccc(c2)Cl)C) naphthyl)sulfonyl]amino}-2-NCCNS(═O)(═O)C oxo-1-pyrrolidinyl]-N-{2-[(methylsulfonyl)amino]ethyl}pro- panamide 29 CHEMBL394714CN(C(═O)[C@@H]1CCCN1S(═O) N-(1-Benzyl-4-piperidinyl)-N-(═O)c1ccc2c(c1)cccc2)C1CCN methyl-1-naphthylsulfonyl)- (CC1)Cc1ccccc1L-prolinamide 30 CHEMBL428576 CC(c1ccc(cc1)S(═O)(═O)N1CCCN-(1-Benzyl-4-piperidinyl)-1- [C@H]1C(═O)NC1CCN(CC1)Cc1ccccc1)C[(4-isopropylphenyl)sulfonyl]-L- prolinamide 31 CHEMBL436413O═C([C@@H]1CCCN1S(═O)(═O) (3S,3aR,6aS)-1- c1cccc2c1cccc2)N1CC[C@H](Cyclopropylcarbonyl)-3- 2[C@H]1[C@H](C)C(═O)N2C(═O)methyl-4-{[(2S)-1-(1- C1CC1 naphthylsulfonyl)-2-pyrrolidinyl]carbonyl}hexahydro pyrrolo[3,2-b]pyrrol-2(1H)-one 32CHEMBL482194 N[C@@H]1CCN(C1)C(═O)[C@H] [(3R)-3-Amino-11CCCCN1S(═O)(═O)c1ccc(cc1)c1ccccc1 pyrrolidinyl][(2R)-1-(4-biphenylylsulfonyl)-2 piperidinyl]methanone 33 CHEMBL523100O═C(N1CCN(CC1)S(═O)(═O) Cyclohexyl[4-(1- c1cccc2c1cccc2)C1CCCCC1naphthylsulfonyl)-1- piperazinyl]methanone 34 CHEMBL525204O═C(N1CCN(CC1(C)C)S(═O)(═O) Cyclohexyl[2,2-dimethyl-4-(1-c1cccc2c1cccc2)C1CCCCC1 naphthylsulfonyl)-1- piperazinyl]methanone

TABLE 10 Specific examples of ADME properties of the selected candidates(Dataset 2) obtained in SwissADME (part 1); in specific examples,Compounds 10, 11, 17, and 18 appeared as good drug candidates, as theyare predicted do not inhibit cytochromes P450 isoforms. Compound # 10 1112 13 14 15 16 17 18 MW 433.52 445.58 407.53 415.51 449.95 463.98 494.65434.53 432.54 #H-bond 6 5 5 5 5 5 5 5 6 acceptors #H-bond 4 4 2 1 1 0 24 5 donors TPSA 145.99 136.76 103.96 95.17 95.17 86.38 95.09 148.16148.79 Consensus 1.04 2.12 2.16 1.91 2.43 2.58 3.55 −0.72 0.56 Log P AliClass Soluble Moderately Moderately Soluble Moderately ModeratelyModerately Soluble Soluble soluble soluble soluble soluble soluble GILow Low High High High High High Low Low absorption BBB No No No No NoNo No No No permeant CYP1A2 No No No No No No No No No inhibitor CYP2C19No No Yes Yes Yes Yes Yes No No inhibitor CYP2C9 No No No Yes Yes Yes NoNo No inhibitor CYP2D6 No No No No Yes Yes Yes No No inhibitor CYP3A4 NoNo Yes Yes Yes Yes Yes No No inhibitor

TABLE 11 Specific examples of ADME properties of the selected candidates(Dataset 2) obtained in SwissADME (part 2). In specific examples,Compounds 19, 22 and 23 appeared as a good drug candidates, as they arepredicted do not inhibit cytochromes P450 isoforms. Compound # 19 20 2122 23 24 25 26 27 28 MW 432.56 512.62 495.59 450.57 446.59 494.49 440.52451.5 494.49 517.02 #H-bond 4 6 6 5 4 9 6 7 9 8 acceptors #H-bond 4 0 03 4 2 2 2 2 3 donors TPSA 138.93 106.69 103.45 147.21 138.93 141.74141.74 165.53 141.74 158.51 Consensus 0.26 2.02 2.38 −0.34 0.84 2.241.53 1.06 2.19 1.08 Log P Ali Class Moderately Moderately ModeratelySoluble Moderately Moderately Moderately Moderately ModeratelyModerately soluble soluble soluble soluble soluble soluble solublesoluble soluble GI High High High Low High Low Low Low Low Lowabsorption BBB No No No No No No No No No No permeant CYP1A2 No No No NoNo No No No No No inhibitor CYP2C19 No No Yes No No Yes No No Yes Noinhibitor CYP2C9 No No Yes No No No No No No No inhibitor CYP2D6 No NoNo No No Yes No No Yes No inhibitor CYP3A4 No Yes Yes No No Yes Yes YesYes Yes inhibitor

TABLE 12 Specific examples of ADME properties of the selected candidates(Dataset 2) obtained in SwissADME (part 3). Compound # 29 30 31 32 33 34MW 491.64 469.64 495.59 413.53 386.51 414.56 #H-bond 5 5 6 5 4 4acceptors #H-bond donors 0 1 0 1 0 0 TPSA 69.31 78.1 103.45 92.09 66.0766.07 Consensus Log 3.56 3.44 2.36 2.26 3.05 3.6 P Ali Class ModeratelyModerately Moderately Soluble Moderately Moderately soluble solublesoluble soluble soluble GI absorption High High High High High High BBBpermeant Yes No No No Yes Yes CYP1A2 No No No No Yes No inhibitorCYP2C19 Yes Yes Yes No Yes Yes inhibitor CYP2C9 Yes Yes Yes No Yes Yesinhibitor CYP2D6 Yes Yes No Yes Yes Yes inhibitor CYP3A4 Yes Yes Yes YesYes Yes inhibitor

Embodiments can additionally or alternatively include applying anysuitable approaches described herein for identification, generation,application, provision, and/or other suitable usage (e.g., intherapeutic compositions, etc.) of any suitable drugs, peptides,proteins, and/or other components, such as for use to prevent attachmentand/or cleavage mediated by H.pylori, and/or thus they can be used aspalliative and/or as a treatment against gastric cancer and/or any othersuitable gastrointestinal conditions, cancers, and/or other suitableconditions.

In embodiments, the method and/or system can include and/or otherwisefunction to determine, generate, provide, and/or otherwise facilitatesmall molecules (e.g., peptides; in form of therapeutic composition(s);etc.) which inhibit the interaction between CagA and E-cadherin (e.g.,such as for diagnostics and/or treatment; etc.), which include one ofthe routes reported for the GC development and/or other suitableconditions.

In embodiments, the method and/or system can include and/or otherwisefunction to inhibit (e.g., through small molecules, drugs, therapeuticcompositions; etc.) the pathway involving binding of CagA (fromH.pylori) and human E-cadherin, which has been described as one of thepathways that induce gastric cancer and/or other suitable conditions.

In embodiments, the method and/or system can include and/or otherwisefunction to design, determine, generate, provide, and/or otherwisefacilitate new peptide-like drugs that can inhibit CagA/E-cadherininteraction (e.g., Since CagA interaction with E-cadherin provokes anabnormal interaction between E-cadherin and β-catenin).

In embodiments, the method and/or system can include and/or otherwisefunction to determine, generate, provide, and/or otherwise facilitatepeptide-like drugs that can be used for treatment and/or as a palliativedrug, such as additionally or alternatively with other treatmentsagainst H. pylori, Gastric Cancer, and/or other suitable conditions.

In specific examples, the method and/or system can include a first stage(and/or performed at any time and/or frequency; etc.), which can includedetermining the sequence(s) of the peptide(s). In specific examples,then (and/or at any suitable time and frequency) in vitro and/or in vivoassays can be used for testing; resulting formulations of peptidesand/or other suitable molecules can be used for gastric cancerdiagnostics and/or treatment.

Specific Examples—Molecular Structures

First (and/or performed at any time and/or frequency; etc.), a molecularstructure of ID (intracellular domain) can be modeled (e.g., homologymodel; etc.) using as template the crystallographic structure ofE-cadherin of Mus musculus (PDB code: 1I7X), and the subsequence ofP12830 from Uniprot as target; however, any suitable molecules and/orcomponents can be used as the template and target.

>sp|P12830|731-882 LRRRAVVKEPLLPPEDDTRDNVYYYDEEGGGEEDQDFDLSQLHRGLDARPEVTRNDVAPTLMSVPRYLPRPANPDEIGNFIDENLKAADTDPTAPPYDSLLVFDYEGSGSEAASLSSLNSSESDKDQDYDYLNEWGNRFKKLADMYGGGE DD

The crystal structure of bacterial virulence protein CagA-CM(particularly the CM domain of CagA) can be obtained from Protein DataBank (PDB code: 3EIC). However, any suitable databases can be used,and/or any suitable templates (e.g., suitable regions, suitable strains,etc.) can be used.

Specific Examples—Molecular Docking

A molecular docking can be performed to model the interaction betweenE-cadherin and CagA at the atomic level, such as for use incharacterizing the particular binding site, of the interaction ofCagA-CM in a non-specific location of CD domain protein. In a specificexample, the docking showed a clear in region corresponding to“DTDPTAPPYDSL” peptide.

However, any suitable docking characterization approaches and/orsuitable in silico approaches and/or other suitable approaches can beperformed for modeling interaction and/or for other suitable purposes.

Specific Examples—Reengineering

Taking into account the above (and/or suitable approaches describedherein), embodiments of the method and/or system can include designinginhibitors of Helicobacter pylori, such as to abolish the GC cell growthand/or oncogenic responses (e.g., based on the inhibition of Citotoxingen A (CagA); etc.). In examples, the method and/or system can includereengineering of “DTDPTAPPYDSL” inhibitory peptide (and/or othersuitable selected peptides, such as based on molecular dockingcharacterization(s); etc.) using a docking method approach; but anysuitable approach can be used for reengineering. The reengineering caninclude mutating any combination of and/or each position of“DTDPTAPPYDSL” peptide for the 19 (and/or other suitable number of)amino acids remaining. Thus, a control docking between the controlpeptide and CagA can be performed. In a specific example, the controldocking resulted in a binding energy of −4.0 kcal/mol. Docking betweenreengineered peptides and CagA was performed. Examples of Results aredescribed in the next table, highlighting the most favorablesubstitutions:

Embodiments can Additionally or Alternatively Include:

-   -   inhibitors of CagA-H. pylori, which are based on peptide        DTDPTAPPYDSL, where:

Position 1: R,H,I,F,P,W,Y Position 2: N Position 3: N,Y Position 4:E,L,Y Position 5: R,L Position 6: S Position 7:R,E,I,L Position 8: I,LWPosition 9: F Position 10: F,W Position 11: A,D,E,H,I,L,Y Position 12:A,N,W,Y.

In some embodiment, the CagA inhibitor has the sequence ofX₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂; wherein:

-   -   X₁ is D, R, H, I, F, P, W, or Y;    -   X₂ is T or N;    -   X₃ is D, N, or Y;    -   X₄ is P, E, L, or Y;    -   X₅ is T, R, or L;    -   X₆ is A or S;    -   X₇ is P, R, E, I, or L;    -   X₈ is P, I, L, or W;    -   X₉ is F, or Y;    -   X₁₀ is D, F, or W;    -   X₁₁ is S, A, D, E, H, I, L, or Y; and    -   X₁₂ is L, A, N, W, or Y.

Embodiments of the present disclosure include peptides having at least80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or 100% identity, to the sequenceof SEQ ID NO: 1-38, listed in Table 13. Embodiments of the presentdisclosure also include peptides having non-natural amino acid.

TABLE 3  peptide sequences SEQ ID No Sequence Binding energy 1DTDPTAPPYDSL −4.0 2 RTDPTAPPYDSL −4.3 3 HTDPTAPPYDSL −4.4 4IDTDPTAPPYDSL −4.3 5 FTDPTAPPYDSL −4.3 6 PTDPTAPPYDSL −4.3 7WTDPTAPPYDSL −4.3 8 YTDPTAPPYDSL −4.7 9 DNDPTAPPYDSL −4.5 10DTNPTAPPYDSL −4.2 11 DTYPTAPPYDSL −4.2 12 DTDEAPPYDSL −4.3 13DTDLTAPPYDSL −4.3 14 DTDYTAPPYDSL −4.5 15 DTDPRAPPYDSL −4.3 16DTDPLAPPYDSL −4.3 17 DTDPTSPPYDSL −4.3 18 DTDPTARPYDSL −4.3 19DTDPTAEPYDSL −4.3 20 DTDPTAIPYDSL −4.4 21 DTDPTALPYDSL −4.3 22DTDPTAPIYDSL −4.4 23 DTDPTAPLYDSL −4.4 24 DTDPTAPWYDSL −4.3 25DTDPTAPPFDSL −4.4 26 DTDPTAPPYFSL −4.5 27 DTDPTAPPYWSL −4.3 28DTDPTAPPYDAL −4.3 29 DTDPTAPPYDDL −4.4 30 DTDPTAPPYDEL −4.3 31DTDPTAPPYDHL −4.3 32 DTDPTAPPYDIL −4.4 33 DTDPTAPPYDLL −4.3 34DTDPTAPPYDYL −4.7 35 DTDPTAPPYDSA −4.2 36 DTDPTAPPYDSN −4.2 37DTDPTAPPYDSW −4.2 38 DTDPTAPPYDSY −4.2

However, any suitable substitutions can be made, such as for improvingbinding energy metrics.

Embodiments of the method and/or system can additionally oralternatively include:

-   -   The use of the aforementioned inhibitors (and/or suitable        molecules described herein, such as molecules derivable from        approaches described herein; etc.) to diagnose and/or treat GC        and/or a health condition wherein H. pylori is involved, and/or        any suitable conditions.    -   The use of the specific inhibitors described herein (and/or        derivable from approaches described herein; etc.) to diagnose        and/or treat GC and/or a health condition wherein H. pylori is        involved, and/or any suitable conditions (e.g., gastrointestinal        conditions; cancer conditions; etc.).    -   A methodology to obtain inhibitors of a protein, wherein the        methodology comprises a modeling of the protein, identifying        binding sites to perform docking of molecules (e.g peptides),        and/or selecting those molecules as best binders to the modeled        protein.    -   One or more therapeutic compositions based on, including, and/or        otherwise associated with one or more peptides, inhibitors,        binding sites, and/or molecules described herein, such as for        facilitating diagnosis and/or therapeutic intervention for GC,        conditions associated with H. pylori, and/or any suitable        conditions (e.g., gastrointestinal conditions; cancer        conditions; etc.).

1. A formulation in pharmaceutically acceptable form suitable for administration to a patient containing an excipient and a HtrA inhibitor having Formula (I):

wherein: R₁ is H, halo, cyano, OH, (C₁-C₆)alkyl, (C₃-C₁₀)heterocyclo, (C₃-C₁₀)cycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with 1 or more R^(w) groups as allowed by valence selected from the groups listed in Table 1; R₂ is H, halo, cyano, OH, (C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₁-C₆)alkoxy, (C₃-C₁₀)heterocyclo, (C₃-C₁₀)cycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with 1 or more R^(w) groups as allowed by valence; R₃ is H, halo, cyano, OH, (C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)carboxyalkyl; N—(C₁-C₆)alkylaminocarbonyl, (C₁-C₆)alkoxy, (C₁-C₆)sulfonyl, (C₃-C₁₀)heterocyclo, (C₃-C₁₀)cycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with 1 or more R^(w) groups as allowed by valence; R₄ is H, halo, cyano, OH, (C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)carboxyalkyl; N—(C₁-C₆)alkylaminocarbonyl, (C₁-C₆)alkoxy, (C₁-C₆)sulfonyl, (C₃-C₁₀)heterocyclo, (C₃-C₁₀)cycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with 1 or more R^(w) groups as allowed by valence; R₅ is H, halo, cyano, OH, (C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)carboxyalkyl; N—(C₁-C₆)alkylaminocarbonyl, (C₁-C₆)alkoxy, (C₁-C₆)sulfonyl, (C₃-C₁₀)heterocyclo, (C₃-C₁₀)cycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with 1 or more R^(w) groups as allowed by valence; R₆ is H, halo, cyano, OH, (C₁-C₆)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)carboxyalkyl; N—(C₁-C₆)alkylaminocarbonyl, (C₁-C₆)alkoxy, (C₁-C₆)sulfonyl, (C₃-C₁₀)heterocyclo, (C₃-C₁₀)cycloalkyl, aryl, or heteroaryl, any of which may be optionally substituted with 1 or more R^(w) groups as allowed by valence; R^(w) at each occurrence is independently H, halo, cyano, nitro, oxo, amino, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more groups selected from the group consisting of halo, cyano, oxo(C₃-C₁₀)heterocyclo, (C₃-C₁₀)cycloalkyl, —(CH₂)_(n)—(C₃-C₁₀) cycloalkyl, —(CH₂)_(n)—(C₃-C₁₀)heterocyclo, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, aryl, and heteroaryl, wherein n is 0, 1, 2, 3, 4, 5, or
 6. 2. The formulation of claim 1, wherein R₁ is selected from the groups listed in Table 1; R₂ is selected from the groups listed in Table 2; R₃ is selected from the groups listed in Table 3; R₄ is selected from the groups listed in Table 4; R₅ is selected from the groups listed in Table 5; and R₆ is selected from the groups listed in Table
 6. 3. The formulation of claim 1, wherein the HtrA inhibitor is selected from the group consisting of: N′-benzyl-N-[2-[(2R)-1-(4-methylphenyl)sulfonylpiperidin-2-yl]ethyl]oxamide; 1-[2-[methyl(naphthalen-2-ylsulfonyl)amino]acetyl]piperidine-4-carboxamide; 8-(4-methylphenyl)sulfonyl-4-(2,4,6-trimethylphenyl)sulfonyl-1-oxa-4,8-diazaspiro[4.5]decane; N-{1-[2-(2-Biphenylyloxy)ethyl]-3-pyrrolidinyl}-3,4-difluorobenzenesulfonamide; 1-(2-Anthrylsulfonyl)-3-piperidinecarboxylic acid; (3S)-1-Carbamimidoyl-N-({(2S)-1-[N-(2-naphthylsulfonyl)glycyl]-2-pyrrolidinyl}methyl)-3-piperidinecarboxamide; (3S)-1-Carbamimidoyl-N-({(2S)-1-[N-(2-naphthylsulfonyl)-L-alanyl]-2-pyrrolidinyl}methyl)-3-piperidinecarboxamide; Cyclohexyl[4-(1-naphthylsulfonyl)-2-(trifluoromethyl)-1-piperazinyl]methanone; and 2-[(8S,11R)-11-{(1R)-1-hydroxy-2-[(3-methylbutyl)(phenylsulfonyl)amino]ethyl}-6,9-dioxo-2-oxa-7,10-diazabicyclo[11.2.2]heptadeca-1(15),13,16-trien-8-yl]acetamide.
 4. A method of treating a bacterial infection comprising administering a pharmaceutically effective amount of the HtrA inhibitor of claim 1 to a human subject in need thereof.
 5. The method of claim 4, wherein the bacterial infection is a Helicobacter pylori infection.
 6. A CagA inhibitor having the sequence of X₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂; wherein: X₁ is D, R, H, I, F, P, W, or Y; X₂ is T or N; X₃ is D, N, or Y; X₄ is P, E, L, or Y; X₅ is T, R, or L; X₆ is A or S; X₇ is P, R, E, I, or L; X₈ is P, I, L, or W; X₉ is F, or Y; X₁₀ is D, F, or W; X₁₁ is S, A, D, E, H, I, L, or Y; and X₁₂ is L, A, N, W, or Y.
 7. The CagA inhibitor of claim 6, having the sequence of DTDPTAPPYDSL.
 8. The CagA inhibitor of claim 6, having the sequence listed in Table
 13. 9. A CagA inhibitor having the sequence at least 80% identity to any of the sequence of SEQ ID NOs: 1-38, listed in Table
 13. 10. A method of treating gastric cancer comprising administering a pharmaceutically effective amount of the CagA inhibitor of claim 6 to a human subject in need thereof.
 11. A method of inhibiting, down-regulating, reducing and/or killing pathogenic bacteria comprising steps of: a. Screening a microorganism that produces an antibacterial compound; b. Conducting structural analysis of the antibacterial compound; c. Modifying the antibacterial compound to improve the affinity to target bacteria.
 12. The method of claim 11, wherein BLAST, FASTA or CLUSTAL is used for sequence analysis in step a).
 13. The method of claim 11, wherein at least one amino acid of the antibacterial compound is mutated in step c).
 14. The method of claim 11, where the structural analysis is performed using solvent-accessible surface area.
 15. The method of claim 11, wherein the antibacterial compound is Salivaricin A, Ruminococcin A, or Bacteriocin staphylococcus
 188. 